Tricyclic heterocycles as BET protein inhibitors

ABSTRACT

The present invention relates to tricyclic heterocycles of Formula (I): 
                         
which are inhibitors of BET proteins such as BRD2, BRD3, BRD4, and BRD-t and are useful in the treatment of diseases such as cancer.

TECHNICAL FIELD

The present disclosure relates to tricyclic heterocycles which areinhibitors of BET proteins such as BRD2, BRD3, BRD4, and BRD-t and areuseful in the treatment of diseases such as cancer.

BACKGROUND

The genomes of eukaryotic organisms are highly organized within thenucleus of the cell. DNA is packaged into chromatin by wrapping around acore of histone proteins to form a nucleosome. These nucleosomes arefurther compacted by aggregation and folding to form a highly condensedchromatin structure. A range of different states of condensation arepossible, and the tightness of this structure varies during the cellcycle, being most compact during the process of cell division. Chromatinstructure plays a critical role in regulating gene transcription byregulating protein access to the DNA. The chromatin structure iscontrolled by a series of post translational modifications to histoneproteins, mainly within the tails of histones H3 and H4 that extendbeyond the core nucleosome structure. These reversible modificationsinclude acetylation, methylation, phosphorylation, ubiquitination andSUMOylation. These epigenetic marks are written and erased by specificenzymes that modify specific residues within the histone tail, therebyforming an epigenetic code. Other nuclear proteins bind to these marksand effect outputs specified by this information through the regulationof chromatin structure and gene transcription. Increasing evidence linksgenetic changes to genes encoding epigenetic modifiers and regulatorsleading to aberrant histone marks in diseases such as neurodegenerativedisorders, metabolic diseases, inflammation and cancer.

Histone acetylation is typically associated with the activation of genetranscription, as the modification weakens the interaction between theDNA and the histone proteins, permitting greater access to DNA by thetranscriptional machinery. Specific proteins bind to acetylated lysineresidues within histones to “read” the epigenetic code. A highlyconserved protein module called the bromodomain binds to acetylatedlysine residues on histone and other proteins. There are more than 60bromodomain-containing proteins in the human genome.

The BET (Bromodomain and Extra-Terminal) family of bromodomaincontaining proteins comprises 4 proteins (BRD2, BRD3, BRD4 and BRD-t)that share a conserved structural organization containing tandemN-terminal bromodomains capable of binding to acetylated lysine residuesof histones and other proteins. BRD2, BRD3 and BRD4 are ubiquitouslyexpressed while BRD-t is restricted to germ cells. BRD proteins playessential, but non-overlapping roles in regulating gene transcriptionand controlling cell growth. BET proteins are associated with largeprotein complexes including Mediator, PAFc and super elongation complexthat regulate many aspects of gene transcription. BRD2 and BRD4 proteinshave been shown to remain in complex with chromosomes during mitosis andare required to promote transcription of critical genes including cyclinD and c-Myc that initiate the cell cycle. Mochizuki et al., J. Biol.Chem. 2008, 283, 9040-9048. BRD4 is essential for recruiting the proteintranslational elongation factor B complex to the promoters of induciblegenes resulting in the phosphorylation of RNA polymerase II andstimulating productive gene transcription and elongation. Jang et al.,Mol. Cell, 2005, 19, 523-534. In some instances, a kinase activity ofBRD4 may directly phosphorylate and activate RNA polymerase II. Devaiahet al., Proc. Nat. Acad. Sci., USA. 2012, 109, 6927-6932. Cells lackingBRD4 show impaired progression through cell cycle. BRD2 and BRD3 arereported to associate with histones along actively transcribed genes andmay be involved in facilitating transcriptional elongation. Leroy etal., Mol. Cell, 2008, 30, 51-60. In addition to acetylated histones, BETproteins have been shown to bind selectively to acetylated transcriptionfactors including the RelA subunit of NF-kB and GATA1 thereby directlyregulating the transcriptional activity of these proteins to controlexpression of genes involved in inflammation and hematopoieticdifferentiation. Huang et al., Mol. Cell Biol., 2009, 29, 1375-1387;Lamonica et al., Proc. Nat. Acad. Sci., USA, 2011, 108, E159-168.

A recurrent translocation involving NUT (nuclear protein in testes) withBRD3 or BRD4 to form a novel fusion oncogene, BRD-NUT, is found in ahighly malignant form of epithelial neoplasia. French et al., CancerRes., 2003, 63, 304-307; French et al., J. Clin. Oncol., 2004, 22,4135-4139. Selective ablation of this oncogene restores normal cellulardifferentiation and reverses the tumorigenic phenotype. Filippakopouloset al., Nature, 2010, 468, 1068-1073. Genetic knockdown of BRD2, BRD3and BRD4 has been shown to impair the growth and viability of a widerange of hematological and solid tumor cells. Zuber et al., Nature,2011, 478, 524-528; Delmore et al., Cell, 2011, 146, 904-917. Aside froma role in cancer, BET proteins regulate inflammatory responses tobacterial challenge, and a BRD2 hypomorph mouse model showeddramatically lower levels of inflammatory cytokines and protection fromobesity induced diabetes. Wang et al., Biochem. J., 2009, 425, 71-83;Belkina et al., J. Immunol. 102838, online publication before print,Feb. 18, 2013. In addition, some viruses make use of these BET proteinsto tether their genomes to the host cell chromatin, as part of theprocess of viral replication or use BET proteins to facilitate viralgene transcription and repression. You et al., Cell, 2004, 117, 349-60;Zhu et al., Cell Reports, 2012, 2, 807-816.

Accordingly, there is a need for compounds that modulate the activity ofthe BET family of proteins, including BRD2, BRD3, and BRD4, that can beused to treat BET protein-associated diseases such as cancer. Thecompounds of the invention help meet this need.

SUMMARY

The present disclosure provides, inter alia, a compound of Formula (I):

or a pharmaceutically acceptable salt thereof; wherein the variables areas defined below.

The present disclosure also provides a composition comprising a compoundof Formula (I), or a pharmaceutically acceptable salt thereof, and atleast one pharmaceutically acceptable carrier.

The present disclosure also provides methods of treating cancer andother diseases comprising administering to a patient a therapeuticallyeffective amount of a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof.

The details of one or more embodiments are set forth in the descriptionbelow. Other features, objects, and advantages will be apparent from thedescription and from the claims.

DETAILED DESCRIPTION

For the terms “e.g.” and “such as,” and grammatical equivalents thereof,the phrase “and without limitation” is understood to follow unlessexplicitly stated otherwise.

The singular forms “a,” “an,” and “the” include plural referents unlessthe context clearly dictates otherwise.

The term “about” means “approximately” (e.g., plus or minusapproximately 10% of the indicated value).

I. Compounds

The present disclosure relates, inter alia, to a compound of a BETprotein-inhibiting compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

represents a single bond or a double bond;

L is CR⁹R^(9a), O, S, SO, or SO₂;

Cy¹ is selected from phenyl or a 5-6 membered heteroaryl groupcomprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S,wherein said phenyl or 5-6 membered heteroaryl of Cy¹ is optionallysubstituted with 1, 2, 3, or 4 groups independently selected from R¹¹;

R¹ and R² are independently selected from H, halo, CN, OH, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, OR^(a1), SR^(a1),C(═O)R^(b1), C(═O)NR^(c1)R^(d1), C(═O)OR^(a1), OC(═O)R^(b1),OC(═O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(═O)R^(b1),NR^(c1)C(═O)NR^(c1)R^(d1), NR^(c1)C(═O)OR^(a1), S(═O)R^(b1),S(═O)NR^(c1)R^(d1), S(═O)₂R^(b1), NR^(c1)S(═O)₂R^(b1) andS(═O)₂NR^(c1)R^(d1), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl of R¹ and R² are optionally substituted with 1, 2, or 3 groupsindependently selected from halo, CN, OH, OR^(a1), SR^(a1), C(═O)R^(b1),C(═O)NR^(c1)R^(d1), C(═O)OR^(a1), OC(═O)R^(b1), OC(═O)NR^(c1)R^(d1),NR^(c1)R^(d1), NR^(c1)C(═O)R^(b1), NR^(c1)C(═O)NR^(c1)R^(d1),NR^(c1)C(═O)OR^(a1) S(═O)R^(b1), S(═O)NR^(c1)R^(d1), S(═O)₂R^(b1),NR^(c1)S(═O)₂R^(b1) and S(═O)₂NR^(c1)R^(d1);

provided neither R¹ nor R² are Cl, Br, I, CN, or OH when L is O or S;

alternatively, R¹ and R² together with the carbon atom to which they areattached are combined to form a C₃₋₇ cycloalkyl group, wherein saidcycloalkyl group is optionally substituted with 1, 2, 3, or 4 groupsindependently selected from R²⁰;

Cy³ is selected from phenyl, C₃₋₇ cycloalkyl, a 5-10 membered heteroarylgroup comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, Oand S, and a 4-10 membered heterocycloalkyl group comprising carbon and1, 2, or 3 heteroatoms selected from N, O and S, wherein said phenyl,C₃₋₇ cycloalkyl, 5-10 membered heteroaryl, and 4-10 memberedheterocycloalkyl of Cy³ is optionally substituted with 1, 2, 3, or 4groups independently selected from R¹³, wherein a ring-forming nitrogenatom of said 5-10 membered heteroaryl group or a ring-forming nitrogenatom of said 4-10 membered heterocycloalkyl group is optionallyoxidized;

R⁴ is H, C(═O)NR^(14a)R^(14b), C(═O)R^(14a), C(═O)OR^(14a), or C₁₋₆alkyl optionally substituted by 1, 2, or 3 substituents independentlyselected from halo, NR^(14a)R^(14b), OR^(14a), SR^(14a), CN,C(═O)R^(14a), C(═O)NR^(14a)R^(14b), C(═O)OR^(14a), OC(═O)R^(14b),OC(═O)NR^(14a)R^(14b), NR^(14a)C(═O)R^(14b),NR^(14a)C(═O)NR^(14a)R^(14b), NR^(14a)C(═O)OR^(14b), S(═O)R^(14a),S(═O)NR^(14a)R^(14b), S(═O)₂R^(14a), NR^(14a)S(═O)₂R^(14b), andS(═O)₂NR^(14a)R^(14b);

R⁵ is selected from ═O and ═S when C

N is a single bond,

alternatively, when C

N is a double bond then R⁵ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, NR^(15a)R^(15b), —C(═O)NR^(15a)R^(15b),—C(═O)OR^(15a), phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl groupcomprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S,and a 4-10 membered heterocycloalkyl group comprising carbon and 1, 2,or 3 heteroatoms selected from N, O and S, wherein said alkyl, phenyl,C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, and 4-10 memberedheterocycloalkyl of R⁵ is optionally substituted by 1, 2, 3, or 4 groupsindependently selected from R¹⁵;

R⁶ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆alkoxy, and C₁₋₆ haloalkyl, wherein said alkyl, alkenyl, and alkynyl ofR⁶ are each optionally substituted by 1, 2, 3, or 4 groups independentlyselected R¹⁶;

alternatively, R⁶ is selected from C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatomsselected from N, O and S, and a 4-7 membered heterocycloalkyl groupcomprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S,wherein said C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10 membered heteroaryl, and4-7 membered heterocycloalkyl of R⁶ are each optionally substituted by1, 2, 3, or 4 groups independently selected R²⁰;

R⁷ is selected from H, halo, CN, OR^(a), NR^(c)R^(d), SR^(b),C(═O)NR^(c)R^(d), C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl groupcomprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S,and a 4-7 membered heterocycloalkyl group comprising carbon and 1, 2, or3 heteroatoms selected from N, O and S, wherein said alkyl, alkenyl,alkynyl, phenyl, cycloalkyl, 5-6 membered heteroaryl group, and a 4-7membered heterocycloalkyl group of R⁷ are optionally substituted with 1,2, or 3 groups independently selected from R¹⁷;

R⁸ is selected from H, C₁₋₃ alkyl, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃haloalkyl, halo, CN, OR^(a), NR^(c)R^(d), SR^(b), and C(═O)NR^(c)R^(d),wherein said C₁₋₃ alkyl of R⁸ is optionally substituted with 1, 2, or 3groups independently selected from R¹⁸;

R⁹ and R^(9a) are independently selected from H, C₁₋₃ alkyl, C₁₋₃haloalkyl, halo, CN, OR^(a), NR^(c)R^(d), SR^(b), and C(═O)NR^(c)R^(d);

R¹¹ is independently at each occurrence selected from H, C₁₋₃ alkyl,C₁₋₃ haloalkyl, halo, CN, OR^(a), NR^(c)R^(d), SR^(b), andC(═O)NR^(c)R^(d), wherein said C₁₋₃ alkyl is optionally substituted byOH;

R¹³ is independently at each occurrence selected from H, halo, CN, OH,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, OR^(a3),SR^(a3), C(═O)R^(b3), C(═O)NR^(c3)R^(d3), C(═O)OR^(a3), OC(═O)R^(b3),OC(═O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(═O)R^(b3),NR^(c3)C(═O)NR^(c3)R^(d3), NR^(c3)C(═O)OR^(a3), S(═O)R^(b3),S(═O)NR^(c3)R^(d3), S(═O)₂R^(b3), NR^(c3)S(═O)₂R^(b3) andS(═O)₂NR^(c3)R^(d3), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl of R¹³ is optionally substituted with 1, 2, or 3 groupsindependently selected from halo, CN, OH, OR^(a3), SR^(a3), C(═O)R^(b3),C(═O)NR^(c3)R^(d3), C(═O)OR^(a3), OC(═O)R^(b3), OC(═O)NR^(c3)R^(d3),NR^(c3)R^(d3), NR^(c3)C(═O)R^(b3), NR^(c3)C(═O)NR^(c3)R^(d3),NR^(c3)C(═O)OR^(a3), S(═O)R^(b3), S(═O)NR^(c3)R^(d3), S(═O)₂R^(b3),NR^(c3)S(═O)₂R^(b3) and S(═O)₂NR^(c3)R^(d3);

R¹⁵ is independently at each occurrence selected from H, C₁₋₆ alkyl,C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 memberedheteroaryl, halo, CN, OR^(a5), SR^(a5), C(═O)R^(b5), C(═O)NR^(c5)R^(d5),C(═O)OR^(a5), OC(═O)R^(b5), OC(═O)NR^(c5)R^(d5), NR^(c5)R^(d5),NR^(c5)C(═O)R^(b5) NR^(c5)C(═O)NR^(c5)R^(d5), NR^(c5)C(═O)OR^(a5),S(═O)R^(b5), S(═O)NR^(c5)R^(d5), S(═O)₂R^(b5), NR^(c5)S(═O)₂R^(b5), andS(═O)₂NR^(c5)R^(d5), wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl are eachoptionally substituted by 1, 2, or 3 substituents independently selectedfrom halo, CN, OR^(a5), SR^(a5), C(═O)R^(b5), C(═O)NR^(c5)R^(d5),C(═O)OR^(a5), OC(═O)R^(b5), OC(═O)NR^(c5)R^(d5), NR^(c5)R^(d5),NR^(c5)C(═O)R^(b5), NR^(c5)C(═O)NR^(c5)R^(d5), NR^(c5)C(═O)OR^(a5),S(═O)R^(b5), S(═O)NR^(c5)R^(d5), S(═O)₂R^(b5), NR^(c5)S(═O)₂R^(b5),S(═O)₂NR^(c5)R^(d5), 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl, and C₃₋₇ cycloalkyl;

R^(14a) and R^(14b) are independently at each occurrence selected from Hand C₁₋₆ alkyl, wherein said C₁₋₆ alkyl of R^(14a) and R^(14b) isoptionally substituted with 1, 2, or 3 substituents selected from R²⁰;

or R^(14a) and R^(14b) together with the N atom to which they areattached form a 4-7 membered heterocycloalkyl ring optionallysubstituted with 1, 2, or 3 substituents selected from R²⁰;

R^(15a) and R^(15b) are independently at each occurrence selected from Hand C₁₋₆ alkyl, wherein said C₁₋₆ alkyl of R^(15a) and R^(15b) isoptionally substituted with 1, 2, or 3 substituents selected from R²⁰;

or R^(15a) and R^(15b) together with the N atom to which they areattached form a 4-7 membered heterocycloalkyl ring optionallysubstituted with 1, 2, or 3 substituents selected from R²⁰;

R¹⁶ is independently at each occurrence selected from halo, CN, OH,OR^(a6), SR^(a6), C(═O)R^(b6), C(═O)NR^(c6)R^(d6), C(═O)OR^(a6),OC(═O)R^(b6), OC(═O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(═O)R^(b6),NR^(c6)C(═O)NR^(c6)R^(d6), NR^(c6)C(═O)OR^(a6), S(═O)R^(b6),S(═O)NR^(c6)R^(d6), S(═O)₂R^(b6), NR^(c6)S(═O)₂R^(b6) andS(═O)₂NR^(c6)R^(d6), C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10 memberedheteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selectedfrom N, O and S, and a 4-7 membered heterocycloalkyl group comprisingcarbon and 1, 2, or 3 heteroatoms selected from N, O and S, wherein saidC₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10 membered heteroaryl, and 4-7 memberedheterocycloalkyl of R¹⁶ are each optionally substituted by 1, 2, 3, or 4groups independently selected R²⁰;

R¹⁷ and R¹⁸ are independently at each occurrence selected from halo,C₁₋₄ alkyl, CN, OR^(a), NR^(c)R^(d), SR^(b), C(═O)NR^(c)R^(d),C(═O)OR^(a), and NR^(c)C(═O)R^(a);

R^(a), R^(c), and R^(d) are independently at each occurrence selectedfrom H, C₁₋₆ alkyl, C(O)R^(e), S(═O)₂R^(f), C(═O)NR^(g)R^(h), and phenyloptionally substituted by C₁₋₄ alkoxy;

R^(b) is at each occurrence C₁₋₆ alkyl;

R^(e) is at each occurrence C₁₋₄ alkyl optionally substituted by a groupselected from phenyl, C₁₋₄ alkoxy, amino, C₁₋₄ alkylamino, and C₂₋₈dialkylamino;

R^(f) is C₁₋₄ alkyl;

R^(g) and R^(h) are independently at each occurrence selected from H andC₁₋₄ alkyl;

R^(a1), R^(b1), R^(c1) and R^(d1) are independently at each occurrenceselected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆haloalkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynylforming R^(a1), R^(b1), R^(c1) and R^(d1) are each optionallysubstituted with 1, 2, or 3 substituents independently selected fromR²⁰;

R^(a3), R^(b3), R^(c3) and R^(d3) are independently at each occurrenceselected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆cycloalkyl, and C₁₋₆ haloalkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,and C₂₋₆ alkynyl forming R^(a3), R^(b3), R^(c3) and R^(d3) are eachoptionally substituted with 1, 2, or 3 substituents independentlyselected from halo, CN, OH, OR^(a4), SR^(a4), C(═O)R^(b4),C(═O)NR^(c4)R^(d4), C(═O)OR^(a4), OC(═O)R^(b4), OC(═O)NR^(c4)R^(d4),NR^(c4)R^(d4) NR^(c4)C(═O)R^(b4), NR^(c4)C(═O)NR^(c4)R^(d4)NR^(c4)C(═O)OR^(a4), S(═O)R^(b4), S(═O)NR^(c4)R^(d4), S(═O)₂R^(b4),NR^(c4)S(═O)₂R^(b4) and S(═O)₂NR^(c4)R^(d4);

R^(a4), R^(b4), R^(c4) and R^(d4) are independently at each occurrenceselected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆haloalkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynylforming R^(a4), R^(b4), R^(c4) and R^(d4) are each optionallysubstituted with 1, 2, or 3 substituents independently selected fromR²⁰;

R^(a5), R^(b5), R^(c5) and R^(d5) are independently at each occurrenceselected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆cycloalkyl, 5-6 membered heterocycloalkyl, and C₁₋₆ haloalkyl whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl forming R^(a5), R^(b5),R^(c5) and R^(d5) are each optionally substituted with 1, 2, or 3substituents independently selected from R²⁰;

or R^(c5) and R^(d5) together with the N atom to which they are attachedform a 4-7 membered heterocycloalkyl ring optionally substituted with 1,2, or 3 substituents independently selected from R²⁰;

R^(a6), R^(c6) and R^(d6) are independently at each occurrence selectedfrom H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkylwherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl forming R^(a6),R^(c6) and R^(d6) are each optionally substituted with 1, 2, or 3substituents independently selected from R²⁰;

alternatively, R^(c6) and R^(d6) together with the nitrogen atom towhich they are attached form a 4-7 membered heterocycloalkyl groupcomprising carbon, nitrogen, and 0, 1, or 2 additional heteroatomsselected from N, O and S, wherein said 4-7 membered heterocycloalkylgroup is optionally substituted with 1, 2, or 3 substituentsindependently selected from R²⁰;

R^(b6) is independently at each occurrence selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatomsselected from N, O and S, and a 4-7 membered heterocycloalkyl groupcomprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S,wherein said alkyl, alkenyl, alkynyl, phenyl, cycloalkyl, 5-6 memberedheteroaryl group, and 4-7 membered heterocycloalkyl group are eachoptionally substituted with 1, 2, or 3 substituents independentlyselected from R²⁰; and

R²⁰ is at each occurrence independently selected from H, halo, OH, CN,amino, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ alkylamino, di(C₁₋₄alkyl)amino, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₁₋₄ alkyl-C(═O)—, C₁₋₄alkyl-C(═O)O—, C₁₋₄ alkyl-OC(═O)—, HOC(═O)—, H₂NC(═O)—, C₁₋₄alkyl-NHC(═O)—, di(C₁₋₄ alkyl)NC(═O)—, C₁₋₄ alkyl-C(═O)NH—, C₁₋₄alkyl-O—C(═O)NH—, C₁₋₄ alkyl-S(═O)—, H₂NS(═O)—, C₁₋₄ alkyl-NHS(═O)—,di(C₁₋₄ alkyl)NS(═O)—, C₁₋₄ alkyl-S(═O)₂—, C₁₋₄ alkyl-S(═O)₂NH—,H₂NS(═O)₂—, C₁₋₄ alkyl-NHS(═O)₂—, and di(C₁₋₄ alkyl)NS(═O)₂—.

The present disclosure relates, inter alia, to a compound of a BETprotein-inhibiting compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

represents a single bond or a double bond;

L is CR⁹R^(9a), O, S, SO, or SO₂;

Cy¹ is selected from phenyl or a 5-6 membered heteroaryl groupcomprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S,wherein said phenyl or 5-6 membered heteroaryl of Cy¹ is optionallysubstituted with 1, 2, 3, or 4 groups independently selected from R¹¹;

R¹ and R² are independently selected from H, halo, CN, OH, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, OR^(a1), SR^(a1),C(═O)R^(b1), C(═O)NR^(c1)R^(d1), C(═O)OR^(a1), OC(═O)R^(b1),OC(═O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(═O)R^(b1),NR^(c1)C(═O)NR^(c1)R^(d1), NR^(c1)C(═O)OR^(a1), S(═O)R^(b1),S(═O)NR^(c1)R^(d1), S(═O)₂R^(b1), NR^(c1)S(═O)₂R^(b1) andS(═O)₂NR^(c1)R^(d1), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl of R¹ and R² are optionally substituted with 1, 2, or 3 groupsindependently selected from halo, CN, OH, OR^(a1), SR^(a1), C(═O)R^(b1),C(═O)NR^(c1)R^(d1), C(═O)OR^(a1), OC(═O)R^(b1), OC(═O)NR^(c1)R^(d1),NR^(c1)R^(d1), NR^(c1)C(═O)R^(b1), NR^(c1)C(═O)NR^(c1)R^(d1),NR^(c1)C(═O)OR^(a1), S(═O)R^(b1), S(═O)NR^(c1)R^(d1), S(═O)₂R^(b1),NR^(c1)S(═O)₂R^(b1) and S(═O)₂NR^(c1)R^(d1);

provided neither R¹ nor R² are Cl, Br, I, CN, or OH when L is O or S;

alternatively, R¹ and R² together with the carbon atom to which they areattached may be combined to form a C₃₋₇ cycloalkyl group, wherein saidcycloalkyl group is optionally substituted with 1, 2, 3, or 4 groupsindependently selected from R²⁰;

Cy³ is selected from phenyl, C₃₋₇ cycloalkyl, a 5-10 membered heteroarylgroup comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, Oand S, and a 4-10 membered heterocycloalkyl group comprising carbon and1, 2, or 3 heteroatoms selected from N, O and S, wherein said phenyl,C₃₋₇ cycloalkyl, 5-10 membered heteroaryl, and 4-10 memberedheterocycloalkyl of Cy³ is optionally substituted with 1, 2, 3, or 4groups independently selected from R¹³, wherein a ring-forming nitrogenatom of said 5-10 membered heteroaryl group or a ring-forming nitrogenatom of said 4-10 membered heterocycloalkyl group is optionallyoxidized;

R⁴ is H or C₁₋₆ alkyl;

R⁵ is selected from ═O and ═S when C

N is a single bond,

alternatively, when C

N is a double bond then R⁵ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, NR^(15a)R^(15b), phenyl, C₃₋₇ cycloalkyl,5-6 membered heteroaryl group comprising carbon and 1, 2, 3 or 4heteroatoms selected from N, O and S, and a 4-7 memberedheterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatomsselected from N, O and S, wherein said alkyl, phenyl, C₃₋₇ cycloalkyl,5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl of R⁵ isoptionally substituted by 1, 2, 3, or 4 groups independently selectedfrom R¹⁵;

R⁶ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆haloalkyl, wherein said alkyl, alkenyl, and alkynyl of R⁶ are eachoptionally substituted by 1, 2, 3, or 4 groups independently selectedR¹⁶;

alternatively, R⁶ is selected from C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatomsselected from N, O and S, and a 4-7 membered heterocycloalkyl groupcomprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S,wherein said C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10 membered heteroaryl, and4-7 membered heterocycloalkyl of R⁶ are each optionally substituted by1, 2, 3, or 4 groups independently selected R²⁰;

R⁷ is selected from H, halo, CN, OR^(a), NR^(c)R^(d), SR^(b),C(═O)NR^(c)R^(d), C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl groupcomprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S,and a 4-7 membered heterocycloalkyl group comprising carbon and 1, 2, or3 heteroatoms selected from N, O and S, wherein said alkyl, alkenyl,alkynyl, phenyl, cycloalkyl, 5-6 membered heteroaryl group, and a 4-7membered heterocycloalkyl group of R⁷ are optionally substituted with 1,2, or 3 groups independently selected from R¹⁷;

R⁸ is selected from H, C₁₋₃ alkyl, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃haloalkyl, halo, CN, OR^(a), NR^(c)R^(d), SR^(b), and C(═O)NR^(c)R^(d),wherein said C₁₋₃ alkyl of R⁸ is optionally substituted with 1, 2, or 3groups independently selected from R¹⁸;

R⁹ and R^(9a) are independently selected from H, C₁₋₃ alkyl, C₁₋₃haloalkyl, halo, CN, OR^(a), NR^(c)R^(d), SR^(b), and C(═O)NR^(c)R^(d);

R¹¹ is independently at each occurrence selected from H, C₁₋₃ alkyl,C₁₋₃ haloalkyl, halo, CN, OR^(a), NR^(c)R^(d), SR^(b), andC(═O)NR^(c)R^(d);

R¹³ is independently at each occurrence selected from H, halo, CN, OH,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, OR^(a3),SR^(a3), C(═O)R^(b3), C(═O)NR^(c3)R^(d3), C(═O)OR^(a3), OC(═O)R^(b3),OC(═O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(═O)R^(b3),NR^(c3)C(═O)NR^(c3)R^(d3), NR^(c3)C(═O)OR^(a3), S(═O)R^(b3),S(═O)NR^(c3)R^(d3), S(═O)₂R^(b3), NR^(c3)S(═O)₂R^(b3) andS(═O)₂NR^(c3)R^(d3), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl of R¹³ is optionally substituted with 1, 2, or 3 groupsindependently selected from halo, CN, OH, OR^(a3), SR^(a3), C(═O)R^(b3),C(═O)NR^(c3)R^(d3), C(═O)OR^(a3), OC(═O)R^(b3), OC(═O)NR^(c3)R^(d3),NR^(c3)R^(d3), NR^(c3)C(═O)R^(b3), NR^(c3)C(═O)NR^(c3)R^(d3),NR^(c3)C(═O)OR^(a3), S(═O)R^(b3), S(═O)NR^(c3)R^(d3), S(═O)₂R^(b3),NR^(c3)S(═O)₂R^(b3) and S(═O)₂NR^(c3)R^(d3);

R¹⁵ is independently at each occurrence selected from H, halo, CN, OH,OR^(a5), SR^(a5), C(═O)R^(b5), C(═O)NR^(c5)R^(d5), C(═O)OR^(a5),OC(═O)R^(b5), OC(═O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(═O)R^(b5),NR^(c5)C(═O)NR^(c5)R^(d5), NR^(c5)C(═O)OR^(a5), S(═O)R^(b5),S(═O)NR^(c5)R^(d5), S(═O)₂R^(b5), NR^(c5)S(═O)₂R^(b5) andS(═O)₂NR^(c5)R^(d5);

R^(15a) and R^(15b) are independently selected from H and C₁₋₆ alkyl,wherein said alkyl of R^(15a) and R^(15b) is optionally substituted with0, 1, 2, or 3 substituents selected from R²⁰;

R¹⁶ is independently at each occurrence selected from halo, CN, OH,OR^(a6), SR^(a6), C(═O)R^(b6), C(═O)NR^(c6)R^(d6), C(═O)OR^(a6),OC(═O)R^(b6), OC(═O)NR^(c6)R^(d6), NR^(c6)R^(d6),NR^(c6)C(═O)R^(b6)NR^(c6)C(═O)NR^(c6)R^(d6), NR^(c6)C(═O)OR^(a6),S(═O)R^(b6), S(═O)NR^(c6)R^(d6), S(═O)₂R^(b6), NR^(c6)S(═O)₂R^(b6) andS(═O)₂NR^(c6)R^(d6), C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10 memberedheteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selectedfrom N, O and S, and a 4-7 membered heterocycloalkyl group comprisingcarbon and 1, 2, or 3 heteroatoms selected from N, O and S, wherein saidC₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10 membered heteroaryl, and 4-7 memberedheterocycloalkyl of R¹⁶ are each optionally substituted by 1, 2, 3, or 4groups independently selected R²⁰;

R¹⁷ and R¹⁸ are independently at each occurrence selected from halo, CN,OR^(a), NR^(c)R^(d) SR^(b), and C(═O)NR^(c)R^(d);

R^(a), R^(c), and R^(d) are independently at each occurrence selectedfrom H and C₁₋₆ alkyl;

R^(b) is at each occurrence C₁₋₆ alkyl;

R^(a1), R^(b1), R^(c1) and R^(d1) are independently at each occurrenceselected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆haloalkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynylforming R^(a1), R^(b1), R^(c1) and R^(d1) are each optionallysubstituted with 1, 2, or 3 substituents independently selected fromR²⁰;

R^(a3), R^(b3), R^(c3) and R^(d3) are independently at each occurrenceselected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆haloalkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynylforming R^(a3), R^(b3), R^(c3) and R^(d3) are each optionallysubstituted with 1, 2, or 3 substituents independently selected fromhalo, CN, OH, OR^(a4), SR^(a4), C(═O)R^(b4), C(═O)NR^(c4)R^(d4),C(═O)OR^(a4), OC(═O)R^(b4), OC(═O)NR^(c4)R^(d4), NR^(c4)R^(d4)NR^(c4)C(═O)R^(b4), NR^(c4)C(═O)NR^(c4)R^(d4) NR^(c4)C(═O)OR^(a4),S(═O)R^(b4), S(═O)NR^(c4)R^(d4), S(═O)₂R^(b4), NR^(c4)S(═O)₂R^(b4) andS(═O)₂NR^(c4)R^(d4);

R^(a4), R^(b4), R^(c4) and R^(d4) are independently at each occurrenceselected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆haloalkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynylforming R^(a4), R^(b4), R^(c4) and R^(d4) are each optionallysubstituted with 1, 2, or 3 substituents independently selected fromR²⁰;

R^(a5), R^(b5), R^(c5) and R^(d5) are independently at each occurrenceselected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆haloalkyl wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynylforming R^(a5), R^(b5), R^(c5) and R^(d5) are each optionallysubstituted with 1, 2, or 3 substituents independently selected fromR²⁰;

R^(a6), R^(c6) and R^(d6) are independently at each occurrence selectedfrom H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkylwherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl forming R^(a6),R^(c6) and R^(d6) are each optionally substituted with 1, 2, or 3substituents independently selected from R²⁰;

alternatively, R^(c6) and R^(d6) together with the nitrogen atom towhich they are attached may be combined to form a 4-7 memberedheterocycloalkyl group comprising carbon, nitrogen, and 0, 1, or 2additional heteroatoms selected from N, O and S, wherein said 4-7membered heterocycloalkyl group is optionally substituted with 1, 2, or3 substituents independently selected from R²⁰;

R^(b6) is independently at each occurrence selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatomsselected from N, O and S, and a 4-7 membered heterocycloalkyl groupcomprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S,wherein said alkyl, alkenyl, alkynyl, phenyl, cycloalkyl, 5-6 memberedheteroaryl group, and 4-7 membered heterocycloalkyl group are eachoptionally substituted with 1, 2, or 3 substituents independentlyselected from R²⁰; and

R²⁰ is at each occurrence independently selected from H, halo, OH, CN,amino, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ alkylamino, di(C₁₋₄alkyl)amino, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₁₋₄ alkyl-C(═O)—, C₁₋₄alkyl-C(═O)O—, C₁₋₄ alkyl-OC(═O)—, HOC(═O)—, H₂NC(═O)—, C₁₋₄alkyl-NHC(═O)—, di(C₁₋₄ alkyl)NC(═O)—, C₁₋₄ alkyl-C(═O)NH—, C₁₋₄alkyl-S(═O)—, H₂NS(═O)—, C₁₋₄ alkyl-NHS(═O)—, di(C₁₋₄ alkyl)NS(═O)—,C₁₋₄ alkyl-S(═O)₂—, C₁₋₄ alkyl-S(═O)₂NH—, H₂NS(═O)₂—, C₁₋₄alkyl-NHS(═O)₂—, and di(C₁₋₄ alkyl)NS(═O)₂—.

In some embodiments of the compounds of Formula (I):

represents a single bond or a double bond;

L is CR⁹R^(9a), O, S, SO, or SO₂;

Cy¹ is selected from phenyl or a 5-6 membered heteroaryl groupcomprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S,wherein said phenyl or 5-6 membered heteroaryl of Cy¹ is optionallysubstituted with 1, 2, 3, or 4 groups independently selected from R¹¹;

R¹ is selected from H, halo, CN, OH, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, OR^(a1), SR^(a1), C(═O)R^(b1),C(═O)NR^(c1)R^(d1), C(═O)OR^(a1), OC(═O)R^(b1), OC(═O)NR^(c1)R^(d1),NR^(c1)R^(d1), NR^(c1)C(═O)R^(b1), NR^(c1)C(═O)NR^(c1)R^(d1),NR^(c1)C(═O)OR^(a1), S(═O)R^(b1), S(═O)NR^(c1)R^(d1), S(═O)₂R^(b1),NR^(c1)S(═O)₂R^(b1) and S(═O)₂NR^(c1)R^(d1), wherein said C₁₋₆ alkyl,C₂₋₆ alkenyl, and C₂₋₆ alkynyl of R¹ and R² are optionally substitutedwith 1, 2, or 3 groups independently selected from halo, CN, OH,OR^(a1), SR^(a1), C(═O)R^(b1), C(═O)NR^(c1)R^(d1), C(═O)OR^(a1),OC(═O)R^(b1), OC(═O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(═O)R^(b1),NR^(c1)C(═O)NR^(c1)R^(d1), NR^(c1)C(═O)OR^(a1), S(═O)R^(b1),S(═O)NR^(c1)R^(d1), S(═O)₂R^(b1), NR^(c1)S(═O)₂R^(b1) andS(═O)₂NR^(c1)R^(d1);

R² is selected from H, halo, CN, OH, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆alkyl-O—, and C₁₋₆ haloalkyl-O—;

provided neither R¹ nor R² are Cl, Br, I, CN, or OH when L is O or S;

Cy³ is selected from phenyl, C₃₋₇ cycloalkyl, a 5-10 membered heteroarylgroup comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, Oand S, and a 4-10 membered heterocycloalkyl group comprising carbon and1, 2, or 3 heteroatoms selected from N, O and S, wherein said phenyl,C₃₋₇ cycloalkyl, 5-10 membered heteroaryl, and 4-10 memberedheterocycloalkyl of Cy³ is optionally substituted with 1, 2, 3, or 4groups independently selected from R¹³; additionally, wherein aring-forming nitrogen atom of said 5-10 membered heteroaryl group or aring-forming nitrogen atom of said 4-10 membered heterocycloalkyl groupis optionally oxidized;

R⁴ is H or C₁₋₆ alkyl;

R⁵ is selected from ═O and ═S when C

N is a single bond,

alternatively, when C

N is a double bond then R⁵ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, NR^(15a)R^(15b), phenyl, C₃₋₇ cycloalkyl,5-6 membered heteroaryl group comprising carbon and 1, 2, 3 or 4heteroatoms selected from N, O and S, and a 4-7 memberedheterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatomsselected from N, O and S, wherein said alkyl, phenyl, C₃₋₇ cycloalkyl,5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl of R⁵ isoptionally substituted by 1, 2, 3, or 4 groups independently selectedfrom R¹⁵;

R⁶ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆haloalkyl, wherein said alkyl, alkenyl, and alkynyl of R⁶ are eachoptionally substituted by 1, 2, 3, or 4 groups independently selectedR¹⁶;

alternatively, R⁶ is selected from C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatomsselected from N, O and S, and a 4-7 membered heterocycloalkyl groupcomprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S,wherein said C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10 membered heteroaryl, and4-7 membered heterocycloalkyl of R⁶ are each optionally substituted by1, 2, 3, or 4 groups independently selected R²⁰;

R⁷ is selected from H, halo, CN, OR^(a), NR^(c)R^(d), SR^(b),C(═O)NR^(c)R^(d), C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl groupcomprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S,and a 4-7 membered heterocycloalkyl group comprising carbon and 1, 2, or3 heteroatoms selected from N, O and S, wherein said alkyl, alkenyl,alkynyl, phenyl, cycloalkyl, 5-6 membered heteroaryl group, and a 4-7membered heterocycloalkyl group of R⁷ are optionally substituted with 1,2, or 3 groups independently selected from R¹⁷;

R⁸ is selected from H, halo, CN, OH, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆alkyl-O—, and C₁₋₆ haloalkyl-O—;

R⁹ and R^(9a) are independently selected from H and C₁₋₃ alkyl;

R¹¹ is independently at each occurrence selected from H, C₁₋₃ alkyl,C₁₋₃ haloalkyl, halo, CN, OR^(a), NR^(c)R^(d), SR^(b), andC(═O)NR^(c)R^(d);

R¹³ is independently at each occurrence selected from H, halo, CN, OH,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, OR^(a3),SR^(a3), C(═O)R^(b3), C(═O)NR^(c3)R^(d3), C(═O)OR^(a3) OC(═O)R^(b3),OC(═O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(═O)R^(b3),NR^(c3)C(═O)NR^(c3)R^(d3), NR^(c3)C(═O)OR^(a3), S(═O)R^(b3),S(═O)NR^(c3)R^(d3), S(═O)₂R^(b3), NR^(c3)S(═O)₂R^(b3) andS(═O)₂NR^(c3)R^(d3), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl of R¹³ is optionally substituted with 1, 2, or 3 groupsindependently selected from halo, CN, OH, OR^(a3), SR^(a3), C(═O)R^(b3),C(═O)NR^(c3)R^(d3), C(═O)OR^(a3)OC(═O)R^(b3), OC(═O)NR^(c3)R^(d3),NR^(c3)R^(d3), NR^(c3)C(═O)R^(b3), NR^(c3)C(═O)NR^(c3)R^(d3),NR^(c3)C(═O)OR^(a3), S(═O)R^(b3), S(═O)NR^(c3)R^(d3), S(═O)₂R^(b3),NR^(c3)S(═O)₂R^(b3) and S(═O)₂NR^(c3)R^(d3);

R¹⁵ is independently at each occurrence selected from H, halo, CN, OH,OR^(a5), SR^(a5), C(═O)R^(b5), C(═O)NR^(c5)R^(d5), C(═O)OR^(a5),OC(═O)R^(b5), OC(═O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(═O)R^(b5),NR^(c5)C(═O)NR^(c5)R^(d5), NR^(c5)C(═O)OR^(a5), S(═O)R^(b5),S(═O)NR^(c5)R^(d5), S(═O)₂R^(b5), NR^(c5)S(═O)₂R^(b5) andS(═O)₂NR^(c5)R^(d5);

R^(15a) and R^(15b) are independently selected from H and C₁₋₆ alkyl,wherein said alkyl of R^(15a) and R^(15b) is optionally substituted with0, 1, 2, or 3 substituents selected from R²⁰;

R¹⁶ is independently at each occurrence selected from halo, CN, OH,OR^(a6), SR^(a6), C(═O)R^(b6), C(═O)NR^(c6)R^(d6), C(═O)OR^(a6),OC(═O)R^(b6), OC(═O)NR^(c6)R^(d6), NR^(c6)R^(d6),NR^(c6)C(═O)R^(b6)NR^(c6)C(═O)NR^(c6)R^(d6), NR^(c6)C(═O)OR^(a6),S(═O)R^(b6), S(═O)NR^(c6)R^(d6), S(═O)₂R^(b6), NR^(c6)S(═O)₂R^(b6) andS(═O)₂NR^(c6)R^(d6), C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10 memberedheteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selectedfrom N, O and S, and a 4-7 membered heterocycloalkyl group comprisingcarbon and 1, 2, or 3 heteroatoms selected from N, O and S, wherein saidC₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10 membered heteroaryl, and 4-7 memberedheterocycloalkyl of R¹⁶ are each optionally substituted by 1, 2, 3, or 4groups independently selected R²⁰;

R¹⁷ is independently at each occurrence selected from halo, CN, OR^(a),NR^(c)R^(d), SR^(b), and C(═O)NR^(c)R^(d);

R^(a), R^(c), and R^(d) are independently at each occurrence selectedfrom H and C₁₋₆ alkyl;

R^(b) is at each occurrence C₁₋₆ alkyl;

R^(a1), R^(b1), R^(c1) and R^(d1) are independently at each occurrenceselected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆haloalkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynylforming R^(a1), R^(b1), R^(c1) and R^(d1) are each optionallysubstituted with 1, 2, or 3 substituents independently selected fromR²⁰;

R^(a3), R^(b3), R^(c3) and R^(d3) are independently at each occurrenceselected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆haloalkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynylforming R^(a3), R^(b3), R^(c3) and R^(d3) are each optionallysubstituted with 1, 2, or 3 substituents independently selected fromhalo, CN, OH, OR^(a4), SR^(a4), C(═O)R^(b4), C(═O)NR^(c4)R^(d4),C(═O)OR^(a4), OC(═O)R^(b4), OC(═O)NR^(c4)R^(d4), NR^(c4)R^(d4)NR^(c4)C(═O)R^(b4), NR^(c4)C(═O)NR^(c4)R^(d4) NR^(c4)C(═O)OR^(a4),S(═O)R^(b4), S(═O)NR^(c4)R^(d4), S(═O)₂R^(b4), NR^(c4)S(═O)₂R^(b4) andS(═O)₂NR^(c4)R^(d4);

R^(a4), R^(b4), R^(c4) and R^(d4) are independently at each occurrenceselected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆haloalkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynylforming R^(a4), R^(b4), R^(c4) and R^(d4) are each optionallysubstituted with 1, 2, or 3 substituents independently selected fromR²⁰;

R^(a5), R^(b5), R^(c5) and R^(d5) are independently at each occurrenceselected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆haloalkyl wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynylforming R^(a)S, R^(b5), R^(c5) and R^(d5) are each optionallysubstituted with 1, 2, or 3 substituents independently selected fromR²⁰;

R^(a6), R^(c6) and R^(d6) are independently at each occurrence selectedfrom H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkylwherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl forming R^(a6),R^(c6) and R^(d6) are each optionally substituted with 1, 2, or 3substituents independently selected from R²⁰;

alternatively, R^(c6) and R^(d6) together with the nitrogen atom towhich they are attached may be combined to form a 4-7 memberedheterocycloalkyl group comprising carbon, nitrogen, and 0, 1, or 2additional heteroatoms selected from N, O and S, wherein said 4-7membered heterocycloalkyl group is optionally substituted with 1, 2, or3 substituents independently selected from R²⁰;

R^(b6) is independently at each occurrence selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatomsselected from N, O and S, and a 4-7 membered heterocycloalkyl groupcomprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S,wherein said alkyl, alkenyl, alkynyl, phenyl, cycloalkyl, 5-6 memberedheteroaryl group, and 4-7 membered heterocycloalkyl group are eachoptionally substituted with 1, 2, or 3 substituents independentlyselected from R²⁰; and

R²⁰ is at each occurrence independently selected from H, halo, OH, CN,amino, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ alkylamino, di(C₁₋₄alkyl)amino, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₁₋₄ alkyl-C(═O)—, C₁₋₄alkyl-C(═O)O—, C₁₋₄ alkyl-OC(═O)—, HOC(═O)—, H₂NC(═O)—, C₁₋₄alkyl-NHC(═O)—, di(C₁₋₄ alkyl)NC(═O)—, C₁₋₄ alkyl-C(═O)NH—, C₁₋₄alkyl-S(═O)—, H₂NS(═O)—, C₁₋₄ alkyl-NHS(═O)—, di(C₁₋₄ alkyl)NS(═O)—,C₁₋₄ alkyl-S(═O)₂—, C₁₋₄ alkyl-S(═O)₂NH—, H₂NS(═O)₂—, C₁₋₄alkyl-NHS(═O)₂—, and di(C₁₋₄ alkyl)NS(═O)₂—.

In some embodiments of the compounds of Formula (I):

represents a single bond or a double bond;

L is O;

Cy¹ is a five membered heteroaryl group comprising carbon and 1, 2, 3 or4 heteroatoms selected from N, O and S, wherein said five memberedheteroaryl of Cy¹ is optionally substituted with 1, 2, or 3 groupsindependently selected from R¹¹;

R¹ is selected from H, F, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, OR^(a1), SR^(a1), C(═O)R^(b1), C(═O)NR^(c1)R^(d1),C(═O)OR^(a1), OC(═O)R^(b1), OC(═O)NR^(c1)R^(d1), NR^(c1)R^(d1),NR^(c1)C(═O)R^(b1), NR^(c1)C(═O)NR^(c1)R^(d1), NR^(c1)C(═O)OR^(a1),S(═O)R^(b1), S(═O)NR^(c1)R^(d1), S(═O)₂R^(b1), NR^(c1)S(═O)₂R^(b1) andS(═O)₂NR^(c1)R^(d1), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl of R¹ and R² are optionally substituted with 1, 2, or 3 groupsindependently selected from halo, CN, OH, OR^(a1), SR^(a1), C(═O)R^(b1),C(═O)NR^(c1)R^(d1), C(═O)OR^(a1), OC(═O)R^(b1), OC(═O)NR^(c1)R^(d1),NR^(c1)R^(d1) NR^(c1)C(O)R^(b1) NR^(c1)C(═O)NR^(c1)R^(d1),NR^(c1)C(═O)OR^(a1), S(═O)R^(b1), S(═O)NR^(c1)R^(d1), S(═O)₂R^(b1),NR^(c1)S(═O)₂R^(b1) and S(═O)₂NR^(c1)R^(d1);

R² is selected from H, F, and C₁₋₆ alkyl;

Cy³ is selected from phenyl, C₃₋₇ cycloalkyl, a 5-10 membered heteroarylgroup comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, Oand S, and a 4-10 membered heterocycloalkyl group comprising carbon and1, 2, or 3 heteroatoms selected from N, O and S, wherein said phenyl,C₃₋₇ cycloalkyl, 5-10 membered heteroaryl, and 4-10 memberedheterocycloalkyl of Cy³ is optionally substituted with 1, 2, 3, or 4groups independently selected from R¹³; additionally, wherein aring-forming nitrogen atom of said 5-10 membered heteroaryl group or aring-forming nitrogen atom of said 4-10 membered heterocycloalkyl groupis optionally oxidized;

R⁴ is H or C₁₋₆ alkyl;

R⁵ is selected from ═O and ═S when C

N is a single bond,

alternatively, when C

N is a double bond then R⁵ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, NR^(15a)R^(15b), phenyl, C₃₋₇ cycloalkyl,5-6 membered heteroaryl group comprising carbon and 1, 2, 3 or 4heteroatoms selected from N, O and S, and a 4-7 memberedheterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatomsselected from N, O and S, wherein said alkyl, phenyl, C₃₋₇ cycloalkyl,5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl of R⁵ isoptionally substituted by 1, 2, 3, or 4 groups independently selectedfrom R¹⁵;

R⁶ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆haloalkyl, wherein said alkyl, alkenyl, and alkynyl of R⁶ are eachoptionally substituted by 1, 2, 3, or 4 groups independently selectedR¹⁶;

R⁷ is selected from H, halo, CN, OR^(a), NR^(c)R^(d), SR^(b),C(═O)NR^(c)R^(d), C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl groupcomprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S,and a 4-7 membered heterocycloalkyl group comprising carbon and 1, 2, or3 heteroatoms selected from N, O and S, wherein said alkyl, alkenyl,alkynyl, phenyl, cycloalkyl, 5-6 membered heteroaryl group, and a 4-7membered heterocycloalkyl group of R⁷ are optionally substituted with 1,2, or 3 groups independently selected from R¹⁷;

R⁸ is selected from H, halo, CN, OH, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆alkyl-O—, and C₁₋₆ haloalkyl-O—;

R¹¹ is independently at each occurrence selected from H, C₁₋₃ alkyl,C₁₋₃ haloalkyl, halo, CN, OR^(a), NR^(c)R^(d), SR^(b), andC(═O)NR^(c)R^(d);

R¹³ is independently at each occurrence selected from H, halo, CN, OH,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, OR^(a3),SR^(a3), C(═O)R^(b3), C(═O)NR^(c3)R^(d3), C(═O)OR^(a3), OC(═O)R^(b3),OC(═O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(═O)R^(b3),NR^(c3)C(═O)NR^(c3)R^(d3), NR^(c3)C(═O)OR^(a3), S(═O)R^(b3),S(═O)NR^(c3)R^(d3), S(═O)₂R^(b3), NR^(c3)S(═O)₂R^(b3) andS(═O)₂NR^(c3)R^(d3), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl of R¹³ is optionally substituted with 1, 2, or 3 groupsindependently selected from halo, CN, OH, OR^(a3), SR^(a3), C(═O)R^(b3),C(═O)NR^(c3)R^(d3), C(═O)OR^(a3), OC(═O)R^(b3), OC(═O)NR^(c3)R^(d3),NR^(c3)R^(d3), NR^(c3)C(═O)R^(b3), NR^(c3)C(═O)NR^(c3)R^(d3),NR^(c3)C(═O)OR^(a3), S(═O)R^(b3), S(═O)NR^(c3)R^(d3), S(═O)₂R^(b3),NR^(c3)S(═O)₂R^(b3) and S(═O)₂NR^(c3)R^(d3);

R¹⁵ is independently at each occurrence selected from H, halo, CN, OH,OR^(a5), SR^(a5), C(═O)R^(b5), C(═O)NR^(c5)R^(d5), C(═O)OR^(a5),OC(═O)R^(b5), OC(═O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(═O)R^(b5),NR^(c5)C(═O)NR^(c5)R^(d5), NR^(c5)C(═O)OR^(a5), S(═O)R^(b5),S(═O)NR^(c5)R^(d5), S(═O)₂R^(b5), NR^(c5)S(═O)₂R^(b5) andS(═O)₂NR^(c5)R^(d5);

R^(15a) and R^(15b) are independently selected from H and C₁₋₆ alkyl,wherein said alkyl of R^(15a) and R^(15b) is optionally substituted with0, 1, 2, or 3 substituents selected from R²⁰;

R¹⁶ is independently at each occurrence selected from halo, CN, OH,OR^(a6), SR^(a6), C(═O)R^(b6), C(═O)NR^(c6)R^(d6), C(═O)OR^(a6),OC(═O)R^(b6), OC(═O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(═O)R^(b6),NR^(c6)C(═O)NR^(c6)R^(d6), NR^(c6)C(═O)OR^(a6), S(═O)R^(b6),S(═O)NR^(c6)R^(d6), S(═O)₂R^(b6), NR^(c6)S(═O)₂R^(b6) andS(═O)₂NR^(c6)R^(d6), C₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10 memberedheteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selectedfrom N, O and S, and a 4-7 membered heterocycloalkyl group comprisingcarbon and 1, 2, or 3 heteroatoms selected from N, O and S, wherein saidC₆₋₁₀ aryl, C₃₋₇ cycloalkyl, 5-10 membered heteroaryl, and 4-7 memberedheterocycloalkyl of R¹⁶ are each optionally substituted by 1, 2, 3, or 4groups independently selected R²⁰;

R¹⁷ is independently at each occurrence selected from halo, CN, OR^(a),NR^(c)R^(d), SR^(b), and C(═O)NR^(c)R^(d);

R^(a), R^(c), and R^(d) are independently at each occurrence selectedfrom H and C₁₋₆ alkyl; R^(b) is at each occurrence C₁₋₆ alkyl;

R^(a1), R^(b1), R^(c1) and R^(d1) are independently at each occurrenceselected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆haloalkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynylforming R^(a1), R^(b1), R^(c1) and R^(d1) are each optionallysubstituted with 1, 2, or 3 substituents independently selected fromR²⁰;

R^(a3), R^(b3), R^(c3) and R^(d3) are independently at each occurrenceselected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆haloalkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynylforming R^(a3), R^(b3), R^(c3) and R^(d3) are each optionallysubstituted with 1, 2, or 3 substituents independently selected fromhalo, CN, OH, OR^(a4), SR^(a4), C(═O)R^(b4), C(═O)NR^(c4)R^(d4),C(═O)OR^(a4), OC(═O)R^(b4), OC(═O)NR^(c4)R^(d4), NR^(c4)R^(d4)NR^(c4)C(═O)R^(b4), NR^(c4)C(═O)NR^(c4)R^(d4) NR^(c4)C(═O)OR^(a4),S(═O)R^(b4), S(═O)NR^(c4)R^(d4), S(═O)₂R^(b4), NR^(c4)S(═O)₂R^(b4) andS(═O)₂NR^(c4)R^(d4);

R^(a4), R^(b4), R^(c4) and R^(d4) are independently at each occurrenceselected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆haloalkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynylforming R^(a4), R^(b4), R^(c4) and R^(d4) are each optionallysubstituted with 1, 2, or 3 substituents independently selected fromR²⁰;

R^(a5), R^(b5), R^(c5) and R^(d5) are independently at each occurrenceselected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆haloalkyl wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynylforming R^(a5), R^(b5), R^(c5) and R^(d5) are each optionallysubstituted with 1, 2, or 3 substituents independently selected fromR²⁰;

R^(a6), R^(c6) and R^(d6) are independently at each occurrence selectedfrom H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkylwherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl forming R^(a6),R^(c6) and R^(d6) are each optionally substituted with 1, 2, or 3substituents independently selected from R²⁰;

alternatively, R^(c6) and R^(d6) together with the nitrogen atom towhich they are attached may be combined to form a 4-7 memberedheterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatomsselected from N, O and S, wherein said 4-7 membered heterocycloalkylgroup is optionally substituted with 1, 2, or 3 substituentsindependently selected from R²⁰;

R^(b6) is independently at each occurrence selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatomsselected from N, O and S, and a 4-7 membered heterocycloalkyl groupcomprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S,wherein said alkyl, alkenyl, alkynyl, phenyl, cycloalkyl, 5-6 memberedheteroaryl group, and 4-7 membered heterocycloalkyl group are eachoptionally substituted with 1, 2, or 3 substituents independentlyselected from R²⁰; and

R²⁰ is at each occurrence independently selected from H, halo, OH, CN,amino, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ alkylamino, di(C₁₋₄alkyl)amino, C₁₋₄ haloalkyl, C₁-4 haloalkoxy, C₁₋₄ alkyl-C(═O)—, C₁₋₄alkyl-C(═O)O—, C₁₋₄ alkyl-OC(═O)—, HOC(═O)—, H₂NC(═O)—, C₁₋₄alkyl-NHC(═O)—, di(C₁₋₄ alkyl)NC(═O)—, C₁₋₄ alkyl-C(═O)NH—, C₁₋₄alkyl-S(═O)—, H₂NS(═O)—, C₁₋₄ alkyl-NHS(═O)—, di(C₁₋₄ alkyl)NS(═O)—,C₁₋₄ alkyl-S(═O)₂—, C₁₋₄ alkyl-S(═O)₂NH—, H₂NS(═O)₂—, C₁₋₄alkyl-NHS(═O)₂—, and di(C₁₋₄ alkyl)NS(═O)₂—.

In some embodiments:

represents a single bond or a double bond;

L is O;

Cy¹ is a five membered heteroaryl group comprising carbon and 1, 2, 3 or4 heteroatoms selected from N, O and S, wherein said five memberedheteroaryl of Cy¹ is optionally substituted with 1, 2, or 3 groupsindependently selected from R¹¹;

R¹ is selected from H, F, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, OR^(a1), C(═O)R^(b1), C(═O)NR^(c1)R^(d1), and C(═O)OR^(a1);

R² is selected from H, F, and C₁₋₆ alkyl;

Cy³ is selected from phenyl, C₃₋₇ cycloalkyl, a 5-10 membered heteroarylgroup comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, Oand S, and a 4-10 membered heterocycloalkyl group comprising carbon and1, 2, or 3 heteroatoms selected from N, O and S, wherein said phenyl,C₃₋₇ cycloalkyl, 5-10 membered heteroaryl, and 4-10 memberedheterocycloalkyl of Cy³ is optionally substituted with 1, 2, 3, or 4groups independently selected from R¹³; additionally, wherein aring-forming nitrogen atom of said 5-10 membered heteroaryl group or aring-forming nitrogen atom of said 4-10 membered heterocycloalkyl groupis optionally oxidized;

R⁴ is H or C₁₋₆ alkyl;

R⁵ is selected from ═O and =S when C

N is a single bond,

alternatively, when C

N is a double bind then R⁵ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, NR^(15a)R^(15b), phenyl, C₃₋₇ cycloalkyl,5-6 membered heteroaryl group comprising carbon and 1, 2, 3 or 4heteroatoms selected from N, O and S, and a 4-7 memberedheterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatomsselected from N, O and S, wherein said alkyl, phenyl, C₃₋₇ cycloalkyl,5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl of R⁵ isoptionally substituted by 1, 2, 3, or 4 groups independently selectedfrom R¹⁵;

R⁶ is selected from H and C₁₋₆ alkyl, wherein said alkyl of R⁶ isoptionally substituted by 1, 2, or 3 groups independently selected R¹⁶;

R⁷ is selected from H, halo, CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, phenyl, and5-6 membered heteroaryl group comprising carbon and 1, 2, 3 or 4heteroatoms selected from N, O and S, wherein said alkyl, phenyl, or 5-6membered heteroaryl group, of R⁷ are optionally substituted with 1, 2,or 3 groups independently selected from R¹⁷;

R⁸ is selected from H, halo, CN, OH, and C₁₋₆ alkyl;

R¹¹ is independently at each occurrence selected from H, C₁₋₃ alkyl,C₁₋₃ haloalkyl, halo, CN, OR^(a), NR^(c)R^(d), SR^(b), andC(═O)NR^(c)R^(d);

R¹³ is independently at each occurrence selected from H, halo, CN, OH,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, OR^(a3),SR^(a3), C(═O)R^(b3), C(═O)NR^(c3)R^(d3), C(═O)OR^(a3), OC(═O)R^(b3),OC(═O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(═O)R^(b3),NR^(c3)C(═O)NR^(c3)R^(d3), NR^(c3)C(═O)OR^(a3), S(═O)R^(b3),S(═O)NR^(c3)R^(d3), S(═O)₂R^(b3), NR^(c3)S(═O)₂R^(b3) andS(═O)₂NR^(c3)R^(d3), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl of R¹³ is optionally substituted with 1, 2, or 3 groupsindependently selected from halo, CN, OH, OR^(a3), SR^(a3), C(═O)R^(b3),C(═O)NR^(c3)R^(d3), C(═O)OR^(a3), OC(═O)R^(b3), OC(═O)NR^(c3)R^(d3),NR^(c3)R^(d3), NR^(c3)C(═O)R^(b3), NR^(c3)C(═O)NR^(c3)R^(d3),NR^(c3)C(═O)OR^(a3), S(═O)R^(b3), S(═O)NR^(c3)R^(d3), S(═O)₂R^(b3),NR^(c3)S(═O)₂R^(b3) and S(═O)₂NR^(c3)R^(d3);

R¹⁵ is independently at each occurrence selected from H, halo, CN, OH,OR^(a5), C(═O)R^(b5), C(═O)NR^(c5)R^(d5), C(═O)OR^(a5), NR^(c5)R^(d5),and NR^(c5)C(═O)R^(b5);

R^(15a) and R^(15b) are independently selected from H and C₁₋₆ alkyl,wherein said alkyl of R^(15a) and R^(15b) is optionally substituted with0, 1, 2, or 3 substituents selected from R²⁰;

R¹⁶ is independently at each occurrence selected from halo, CN, OH,OR^(a6), C(═O)R^(b6), C(═O)NR^(c6)R^(d6), C(═O)OR^(a6), OC(═O)R^(b6),NR^(c6)R^(d6), NR^(c6)C(═O)R^(b6), and a 4-7 membered heterocycloalkylgroup comprising carbon and 1, 2, or 3 heteroatoms selected from N, Oand S, wherein said 4-7 membered heterocycloalkyl of R¹⁶ is optionallysubstituted by 1, 2, 3, or 4 groups independently selected R²⁰;

R¹⁷ is independently at each occurrence selected from halo, CN, OR^(a),NR^(c)R^(d), SR^(b), and C(═O)NR^(c)R^(d);

R^(a), R^(c), and R^(d) are independently at each occurrence selectedfrom H and C₁₋₆ alkyl;

R^(b) is at each occurrence C₁₋₆ alkyl;

R^(a1), R^(b1), R^(c1) and R^(d1) are independently at each occurrenceselected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆haloalkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynylforming R^(a1), R^(b1), R^(c1) and R^(d1) are each optionallysubstituted with 1, 2, or 3 substituents independently selected fromR²⁰;

R^(a3), R^(b3), R^(c3) and R^(d3) are independently at each occurrenceselected from H and C₁₋₆ alkyl, wherein said C₁₋₆ alkyl forming R^(a3),R^(b3), R^(c3) and R^(d3) is optionally substituted with 1, 2, or 3substituents independently selected from halo, CN, OH, OR^(a4), SR^(a4),C(═O)R^(b4), C(═O)NR^(c4)R^(d4), C(═O)OR^(a4), OC(═O)R^(b4),OC(═O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(═O)R^(b4),NR^(c4)C(═O)NR^(c4)R^(d4), NR^(c4)C(═O)OR^(a4), S(═O)R^(b4),S(═O)NR^(c4)R^(d4), S(═O)₂R^(b4), NR^(c4)S(═O)₂R^(b4) andS(═O)₂NR^(c4)R^(d4);

R^(a4), R^(b4), R^(c4) and R^(d4) are independently at each occurrenceselected from H and C₁₋₆ alkyl, wherein said C₁₋₆ alkyl forming R^(a4),R^(b4), R^(c4) and R^(d4) is optionally substituted with 1, 2, or 3substituents independently selected from R²⁰;

R^(a5), R^(b5), R^(c5) and R^(d5) are independently at each occurrenceselected from H and C₁₋₆ alkyl, wherein said C₁₋₆ alkyl forming R^(a5),R^(b5), R^(c5) and R^(d5) is optionally substituted with 1, 2, or 3substituents independently selected from R²⁰;

R^(a6), R^(c6) and R^(d6) are independently at each occurrence selectedfrom H and C₁₋₆ alkyl;

alternatively, R^(c6) and R^(d6) together with the nitrogen atom towhich they are attached may be combined to form a 4-7 memberedheterocycloalkyl group comprising carbon, nitrogen, and 0, 1, or 2additional heteroatoms selected from N, O and S, wherein said 4-7membered heterocycloalkyl group is optionally substituted with 1, 2, or3 substituents independently selected from R²⁰;

R^(b6) is independently at each occurrence selected from C₁₋₆ alkyl; and

R²⁰ is at each occurrence independently selected from H, halo, OH, CN,amino, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ alkylamino, di(C₁₋₄alkyl)amino, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₁₋₄ alkyl-C(═O)—, C₁₋₄alkyl-C(═O)O—, C₁₋₄ alkyl-OC(═O)—, HOC(═O)—, H₂NC(═O)—, C₁₋₄alkyl-NHC(═O)—, di(C₁₋₄ alkyl)NC(═O)—, C₁₋₄ alkyl-C(═O)NH—, C₁₋₄alkyl-S(═O)—, H₂NS(═O)—, C₁₋₄ alkyl-NHS(═O)—, di(C₁₋₄ alkyl)NS(═O)—,C₁₋₄ alkyl-S(═O)₂—, C₁₋₄ alkyl-S(═O)₂NH—, H₂NS(═O)₂—, C₁₋₄alkyl-NHS(═O)₂—, and di(C₁₋₄ alkyl)NS(═O)₂—.

In some embodiments of the compounds of Formula (I), the compound is acompound of Formula (Ia):

or a pharmaceutically acceptable salt thereof, wherein:

represents a single bond or a double bond;

Cy¹ is selected from isoxazolyl and pyrazolyl, wherein said isoxazolyland pyrazolyl of Cy¹ is optionally substituted with 1 or 2 groupsindependently selected from R¹¹;

R¹ is selected from H, methyl, —C(═O)OCH₂CH₃, —C(═O)N(H)CH₂CH₃,—C(═O)N(H)CH₂CH₂OH, and —C(═O)N(CH₃)₂;

Cy³ is selected from phenyl, pyridinyl, oxidopyridinyl, thiazolyl,cyclohexyl, dihydrobenzofuranyl and tetrahydrofuranyl, wherein saidphenyl, pyridinyl, oxidopyridinyl, thiazolyl, cyclohexyl,dihydrobenzofuranyl and tetrahydrofuranyl of Cy³ is optionallysubstituted with 1, 2, 3, or 4 groups independently selected from R¹³;

R⁵ is ═O when C

N is a single bond,

alternatively, when C

N is a double bond then R⁵ is H, methyl, —CH═CH₂, —N(H)CH₃, —N(H)CH₂CH₃,—N(H)CH(CH₃)₂, —N(CH₃)₂, —N(H)CH₂CH₂OH, —N(H)CH(CH₃)CH₂OH,—N(H)CH₂CH(OH)CH₃, —N(H)C(CH₃)₂CH₂OH, —N(CH₃)CH₂CH₂OH, morpholinyl,pyrrolidinyl, hydroxypyrrolidinyl, piperidinyl, hydroxypiperidinyl,azetidinyl, hydroxyazetidinyl, piperazinyl, butoxycarbonylpiperazinyl,and phenyl;

R⁶ is selected from H, methyl, ethyl, and propyl wherein said methyl,ethyl, and propyl of R⁶ are each optionally substituted by 1, 2, or 3groups independently selected R¹⁶;

R⁷ is selected from H, F, Cl, Br, methyl, methoxy, ethoxy, CN, phenyl,and pyridinyl;

R¹¹ is independently at each occurrence selected from H, methyl, ethyl,chloro, and methoxy;

R¹³ is independently at each occurrence selected from H, F, CN, methoxy,—CF₃, —OCH₂C(═O)OH, —OCH₂C(═O)N(H)CH₂CH₃, —OCH₂C(═O)N(H)CH₂CH₂OH, and—OCH₂C(═O)N(CH₃)₂; and

R¹⁶ is independently at each occurrence selected from H, morpholinyl,and piperidinyl.

In some embodiments of the compounds described above, L is O.

In some embodiments, L is S.

In some embodiments, L is CR⁹R^(9a).

In some embodiments, L is CH₂.

In some embodiments, Cy¹ is isoxazolyl substituted with 1 or 2 groupsindependently selected from R¹¹.

In some embodiments, Cy¹ is pyrazolyl substituted with 1 or 2 groupsindependently selected from R¹¹.

In some embodiments, R¹ is selected from H, methyl, —CH₂OH,—C(═O)OCH₂CH₃, —C(═O)N(H)CH₂CH₃, —C(═O)N(H)CH₃, —C(═O)NH₂,—C(═O)N(H)CH₂CH₂OH, and —C(═O)N(CH₃)₂.

In some embodiments, R¹ is selected from H, methyl, —C(═O)OCH₂CH₃,—C(═O)N(H)CH₂CH₃, —C(═O)N(H)CH₂CH₂OH, and —C(═O)N(CH₃)₂.

In some embodiments, R¹ is H.

In some embodiments, R¹ is methyl.

In some embodiments, R¹ is —C(═O)OCH₂CH₃.

In some embodiments, R¹ is C(═O)N(H)CH₂CH₃.

In some embodiments, R¹ is C(═O)N(H)CH₂CH₂OH.

In some embodiments, R¹ is —C(═O)N(CH₃)₂.

In some embodiments, R¹ is —C(═O)N(H)CH₃.

In some embodiments, R¹ is —C(═O)NH₂.

In some embodiments, R¹ is —CH₂OH.

In some embodiments, R² is H.

In some embodiments, R² is methyl.

In some embodiments, Cy³ is selected from phenyl, pyridinyl,oxidopyridinyl, thiazolyl, cyclohexyl, dihydrobenzofuranyl,tetrahydrofuranyl, and piperinyl, wherein said phenyl, pyridinyl,oxidopyridinyl, thiazolyl, cyclohexyl, dihydrobenzofuranyl,tetrahydrofuranyl, and piperidinyl of Cy³ is optionally substituted with1, 2, 3, or 4 groups independently selected from R¹³.

In some embodiments, Cy³ is selected from phenyl, pyridinyl,oxidopyridinyl, thiazolyl, cyclohexyl, dihydrobenzofuranyl andtetrahydrofuranyl, wherein said phenyl, pyridinyl, oxidopyridinyl,thiazolyl, cyclohexyl, dihydrobenzofuranyl and tetrahydrofuranyl of Cy³is optionally substituted with 1, 2, 3, or 4 groups independentlyselected from R¹³.

In some embodiments, Cy³ is phenyl optionally substituted with 1, 2, 3,or 4 groups independently selected from R¹³.

In some embodiments, Cy³ is pyridinyl optionally substituted with 1, 2,3, or 4 groups independently selected from R¹³.

In some embodiments, Cy³ is oxidopyridinyl optionally substituted with1, 2, 3, or 4 groups independently selected from R¹³.

In some embodiments, Cy³ is thiazolyl optionally substituted with 1, 2,3, or 4 groups independently selected from R¹³.

In some embodiments, Cy³ is cyclohexyl optionally substituted with 1, 2,3, or 4 groups independently selected from R¹³.

In some embodiments, Cy³ is dihydrobenzofuranyl optionally substitutedwith 1, 2, 3, or 4 groups independently selected from R¹³.

In some embodiments, Cy³ is tetrahydrofuranyl optionally substitutedwith 1, 2, 3, or 4 groups independently selected from R¹³.

In some embodiments, Cy³ is piperidinyl optionally substituted with 1,2, 3, or 4 groups independently selected from R¹³.

In some embodiments, R⁴ is H, —C(═O)NH₂, —CH₂NH₂, —CH₂N(H)C(═O)CH₃,—C(═O)N(H)CH₃, —CH₂CH₃, or —CH₃.

In some embodiments, R⁴ is H.

In some embodiments, R⁵ is ═O when C

N is a single bond.

In some embodiments, R⁵ is ═S when C

N is a single bond.

In some embodiments, when C

N is a double bond then R⁵ is selected from H, C₁₋₄ alkyl, —CH═CH₂,NR^(15a)R^(15b), —C(═O)NR^(15a)R^(15b), phenyl, and a 4-10 memberedheterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatomsselected from N, O and S, wherein said alkyl, and 4-10 memberedheterocycloalkyl of R⁵ is optionally substituted by 1 or 2 groupsindependently selected from R¹⁵.

In some embodiments, when C

N is a double bond then R⁵ is selected from H, C₁₋₄ alkyl, —CH═CH₂,NR^(15a)R^(15b), —C(═O)R^(15a)R^(15b), phenyl, azetidinyl, pyrrolidinyl,piperidinyl, piperazinyl, 1,2,3,6-tetrahydropyridinyl,2,5-dihydro-1H-pyrrolyl, 1,4-diazepanyl, morpholinyl, andoctahydropyrrolo[1,2-a]pyrazinyl, wherein said C₁₋₄ alkyl, phenyl,azetidinyl, pyrolidinyl, piperidinyl, piperazinyl,1,2,3,6-tetrahydropyridinyl, 2,5-dihydro-1H-pyrrolyl, 1,4-diazepanyl,morpholinyl, and octahydropyrrolo[1,2-a]pyrazinyl of R⁵ is optionallysubstituted by 1 or 2 groups independently selected from R¹⁵.

In some embodiments, when C

N is a double bond then R⁵ is H, methyl —CH═CH₂, —N(H)CH₃, —N(H)CH₂CH₃,—N(H)CH(CH₃)₂, —N(CH₃)₂, —N(H)CH₂CH₂OH, —N(H)CH(CH₃)CH₂OH,—N(H)CH₂CH(OH)CH₃, —N(H)C(CH₃)₂CH₂OH, —N(CH₃)CH₂CH₂OH, morpholinyl,pyrrolidinyl, hydroxypyrrolidinyl, piperidinyl, hydroxypiperidinyl,azetidinyl, hydroxyazetidinyl, piperazinyl, butoxycarbonylpiperazinyl,or phenyl.

In some embodiments, when C

N is a double bond then R⁵ is selected from a 4-6 memberedheterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatomsselected from N, O and S, wherein said 4-6 membered heterocycloalkyl ofR⁵ is optionally substituted by 1 or 2 groups independently selectedfrom R¹⁵.

In some embodiments, when C

N is a double bond then R⁵ is pyrrolidinyl, piperidinyl, azetidinyl, orpiperazinyl, wherein said pyrrolidinyl, piperidinyl, azetidinyl, orpiperazinyl of R⁵ is optionally substituted by 1 or 2 groupsindependently selected from R¹⁵.

In some embodiments, when C

N is a double bond than R⁵ is pyrrolidinyl, wherein said pyrrolidinyl ofR⁵ is optionally substituted by 1 or 2 groups independently selectedfrom R¹⁵.

In some embodiments, when C

N is a double bond then R⁵ is piperidinyl, wherein said piperidinyl ofR⁵ is optionally substituted by 1 or 2 groups independently selectedfrom R¹⁵.

In some embodiments, when C

N is a double bond then R⁵ is azetidinyl, wherein said azetidinyl of R⁵is optionally substituted by 1 or 2 groups independently selected fromR¹⁵.

In some embodiments, when C

N is a double bond then R⁵ is piperazinyl, wherein said piperazinyl ofR⁵ is optionally substituted by 1 or 2 groups independently selectedfrom R¹⁵.

In some embodiments, R¹⁵ is independently at each occurrence selectedfrom C₁₋₆ alkyl, CN, OR^(a5), C(═O)R^(b5), C(═O)NR^(c5)R^(d5),C(═O)OR^(a5), NR^(c5)R^(d5), NR^(c5)C(═O)R^(b5),NR^(c5)C(═O)NR^(c5)R^(d5), NR^(c5)C(═O)OR^(a5), S(═O)₂R^(b5),NR^(c5)S(═O)₂R^(b5), and S(═O)₂NR^(c5)R^(d5), wherein said C₁₋₆ alkyl,is optionally substituted by 1, 2, or 3 substituents independentlyselected from halo, CN, OR^(a5), SR^(a5), C(═O)R^(b5),C(═O)NR^(c5)R^(d5), C(═O)OR^(a5), OC(═O)R^(b5), OC(═O)NR^(c5)R^(d5),NR^(c5)R^(d5), NR^(c5)C(═O)R^(b5), NR^(c5)C(═O)NR^(c5)R^(d5),NR^(c5)C(═O)OR^(a5), S(═O)R^(b5), S(═O)NR^(c5)R^(d5), S(═O)₂R^(b5),NR^(c5)S(═O)₂R^(b5), S(═O)₂NR^(c5)R^(d5), 5-6 membered heteroaryl, 4-7membered heterocycloalkyl, phenyl, and C₃₋₇ cycloalkyl.

In some embodiments, R⁶ is H, C₁₋₄ alkyl, or C₁₋₄ alkoxy.

In some embodiments, R⁶ is H, methyl, or methoxy.

In some embodiments, R⁶ is H.

In some embodiments, R⁷ is selected from H, halo, CN, NR^(c)R^(d), C₁₋₆alkyl, C₂₋₆ alkenyl, 5-6 membered heteroaryl group comprising carbon and1, 2, 3 or 4 heteroatoms selected from N, O and S, and a 5-6 memberedheterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatomsselected from N, O and S, wherein said alkyl, alkenyl, 5-6 memberedheteroaryl group, and 5-6 membered heterocycloalkyl group of R⁷ areoptionally substituted with 1, 2, or 3 groups independently selectedfrom R¹⁷.

In some embodiments, R⁷ is selected from H, F, Cl, Br, CN, NR^(c)R^(d),C₁₋₄ alkyl, C₂₋₄ alkenyl, pyrazolyl, pyridinyl, pyrimidinyl, and1,2,3,6-tetrahydropyridinyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,pyrazolyl, pyridinyl, pyrimidinyl, and 1,2,3,6-tetrahydropyridinyl of R⁷are optionally substituted with 1, 2, or 3 groups independently selectedfrom R¹⁷.

In some embodiments, R⁷ is selected from H, halo, C₁₋₄ alkyl, and CN.

In some embodiments, R⁷ is selected from H, Br, methyl, and CN.

In some embodiments, R⁷ is H.

In some embodiments, R⁷ is Br.

In some embodiments, R⁷ is methyl.

In some embodiments, R⁷ is CN.

In some embodiments, R⁸ is selected from H, halo, C₁₋₄ alkyl, and CN.

In some embodiments, R⁸ is H.

It is understood that when C

N is a double bond then R⁶ is absent.

In some embodiments of the compounds of Formula (I), the compound isselected from the following compounds:

-   7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;-   (4R)-7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;-   (4S)-7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;-   7-(3,5-dimethylisoxazol-4-yl)-1-methyl-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;-   7-(3,5-dimethylisoxazol-4-yl)-5-methyl-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;-   4-[7-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]benzonitrile;-   7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-3-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;-   7-(3,5-dimethylisoxazol-4-yl)-4-(3-methoxyphenyl)-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;-   7-(3,5-dimethylisoxazol-4-yl)-4-(2-methoxyphenyl)-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;-   7-(3,5-dimethylisoxazol-4-yl)-4-(2,4-difluorophenyl)-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;-   7-(3,5-dimethylisoxazol-4-yl)-2-methyl-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;-   7-(3,5-dimethylisoxazol-4-yl)-1-(2-morpholin-4-ylethyl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;-   7-(3,5-dimethyl-1H-pyrazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;-   7-(3-methyl-1H-pyrazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;-   7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;-   (4R)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;-   (4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;-   7-(3,5-dimethylisoxazol-4-yl)-4-(1-oxidopyridin-2-yl)-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;-   4-cyclohexyl-7-(3,5-dimethylisoxazol-4-yl)-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;-   7-(3,5-dimethylisoxazol-4-yl)-4-(tetrahydrofuran-2-yl)-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;-   7-(3,5-dimethylisoxazol-4-yl)-4-(5-fluoropyridin-2-yl)-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;-   ethyl    7-(3,5-dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-5-carboxylate;-   7-(3,5-dimethylisoxazol-4-yl)-4-(1,3-thiazol-2-yl)-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;-   2-{2-[7-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]phenoxy}-N-ethylacetamide;-   ethyl    7-(3,5-dimethylisoxazol-4-yl)-2-oxo-4-phenyl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-5-carboxylate;-   7-(3,5-dimethylisoxazol-4-yl)-N-ethyl-2-oxo-4-phenyl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-5-carboxamide;-   7-(3,5-dimethylisoxazol-4-yl)-N-isopropyl-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-amine;-   7-(3,5-dimethylisoxazol-4-yl)-N-methyl-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-amine;-   7-(3,5-dimethylisoxazol-4-yl)-N-ethyl-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-amine;-   7-(3,5-dimethylisoxazol-4-yl)-N,N-dimethyl-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-amine;-   2-{[7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]amino}ethanol;-   2-{[7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]amino}propan-1-ol;-   1-{[7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]amino}propan-2-ol;-   2-{[7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]amino}-2-methylpropan-1-ol;-   2-[[7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl](methyl)amino]ethanol;-   7-(1-methyl-1H-pyrazol-5-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;-   9-bromo-7-(1-methyl-1H-pyrazol-5-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;-   9-methyl-7-(1-methyl-1H-pyrazol-5-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;-   7-(4-chloro-1-methyl-1H-pyrazol-5-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;-   7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;-   7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-2-piperazin-1-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;-   7-(3,5-dimethylisoxazol-4-yl)-2,4-diphenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;-   7-(3,5-dimethylisoxazol-4-yl)-2-oxo-4-phenyl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-9-carbonitrile;-   7-(3,5-dimethylisoxazol-4-yl)-4,9-diphenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;-   7-(1,4-dimethyl-1H-pyrazol-5-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;-   9-bromo-7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;-   7-(3,5-dimethylisoxazol-4-yl)-9-methyl-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;-   7-(3,5-dimethylisoxazol-4-yl)-N,N-dimethyl-2-oxo-4-phenyl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-5-carboxamide;-   7-(3,5-dimethylisoxazol-4-yl)-N-(2-hydroxyethyl)-2-oxo-4-phenyl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-5-carboxamide;-   7-(3,5-dimethylisoxazol-4-yl)-4-(4-fluorophenyl)-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;-   2-{2-[7-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]phenoxy}-N-(2-hydroxyethyl)acetamide;-   2-{2-[7-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]phenoxy}-N,N-dimethylacetamide;-   7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-9-pyridin-3-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;-   7-(3,5-dimethylisoxazol-4-yl)-2-morpholin-4-yl-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;-   7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-2-pyrrolidin-1-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;-   1-[7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-ol;-   7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-2-piperidin-1-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;-   1-[7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperidin-4-ol;-   1-[7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperidin-3-ol;-   1-[7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]azetidin-3-ol;    and-   4-[7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperazine-1-carboxylate;

or a pharmaceutically acceptable salt thereof.

In some embodiments of the compounds of Formula (I), the compound isselected from the following compounds:

-   7-(3,5-Dimethylisoxazol-4-yl)-5,5-dimethyl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;-   7-(3,5-Dimethylisoxazol-4-yl)-5-(hydroxymethyl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;-   7-(3,5-Dimethylisoxazol-4-yl)-4-piperidin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;-   4-(1-Acetylpiperidin-2-yl)-7-(3,5-dimethylisoxazol-4-yl)-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;-   [7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]methyl    acetate;-   7-(3,5-Dimethylisoxazol-4-yl)-4-(hydroxymethyl)-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;-   7-(3,5-Dimethylisoxazol-4-yl)-4-methyl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;-   7-(3,5-Dimethylisoxazol-4-yl)-4-ethyl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;-   7-(3,5-Dimethylisoxazol-4-yl)-N-methyl-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-4-carboxamide;-   N-{[7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]methyl}acetamide;-   4-(Aminomethyl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;-   7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-4-carboxamide;-   7-(3,5-dimethylisoxazol-4-yl)-5-methyl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;-   7-(3,5-dimethylisoxazol-4-yl)-N-methyl-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-5-carboxamide;-   7-(3,5-dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-5-carboxamide;-   7-(3,5-dimethylisoxazol-4-yl)-4-(5-fluoropyridin-3-yl)-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;-   7-(3,5-dimethylisoxazol-4-yl)-4-[1-(methylsulfonyl)piperidin-2-yl]-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;-   2-[7-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]-N-isopropylpiperidine-1-carboxamide;-   (4S)-7-(3,5-dimethylisoxazol-4-yl)-9-(1-methyl-1H-pyrazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;-   5-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-9-yl]-N,N-dimethylpyridine-2-carboxamide;-   tert-butyl    4-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-9-yl]-3,6-dihydropyridine-1(2H)-carboxylate;-   (4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-9-pyrimidin-5-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;-   (4S)-7-(3,5-dimethylisoxazol-4-yl)-9-(1-methyl-1H-pyrazol-5-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;-   ethyl    (2E)-3-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-9-yl]acrylate;-   (4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-9-(1,2,3,6-tetrahydropyridin-4-yl)-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;-   (4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-2-vinyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;-   (1R)-1-[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]ethane-1,2-diol;-   1-[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]ethanol;-   (4S)-7-(3,5-Dimethylisoxazol-4-yl)-N,N-dimethyl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine-2-carboxamide;-   (4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;-   tert-Butyl    (4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine-2-carboxylate;-   (4S)-7-(3,5-Dimethylisoxazol-4-yl)-2-(morpholin-4-ylcarbonyl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;-   (4S)-7-(3,5-Dimethylisoxazol-4-yl)-N-methyl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine-2-carboxamide;-   (4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine-2-carboxamide;-   tert-Butyl    4-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]-3,6-dihydropyridine-1(2H)-carboxylate;-   tert-Butyl    3-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]-2,5-dihydro-1H-pyrrole-1-carboxylate;-   tert-Butyl    5-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]-3,6-dihydropyridine-1(2H)-carboxylate;-   tert-Butyl    4-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperidine-1-carboxylate;-   tert-Butyl    3-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidine-1-carboxylate;-   tert-Butyl    3-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperidine-1-carboxylate;-   (4S)-2-(1-Acetylpiperidin-4-yl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;-   (4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-2-(1,2,3,6-tetrahydropyridin-4-yl)-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;-   (4S)-2-(2,5-dihydro-1H-pyrrol-3-yl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;-   (4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-2-pyrrolidin-3-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;-   (4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-2-(1,2,5,6-tetrahydropyridin-3-yl)-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;-   (4S)-7-(3,5-dimethylisoxazol-4-yl)-2-piperidin-3-yl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;-   (4S)-2-(1-Acetylpiperidin-4-yl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;-   (4S)-2-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;-   (4S)-2-[1-(cyclopropylcarbonyl)piperidin-4-yl]-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;-   (4S)-7-(3,5-dimethylisoxazol-4-yl)-2-[1-(methylsulfonyl)piperidin-4-yl]-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;-   (4S)-2-(1-acetylpyrrolidin-3-yl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;-   (4S)-2-[1-(cyclopropylcarbonyl)pyrrolidin-3-yl]-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;-   (4S)-7-(3,5-dimethylisoxazol-4-yl)-2-[1-(methylsulfonyl)pyrrolidin-3-yl]-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;-   (4S)-2-(1-acetyl-1,2,5,6-tetrahydropyridin-3-yl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;-   (4S)-2-(1-acetylpiperidin-3-yl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;-   (4S)-2-[1-(cyclopropylcarbonyl)piperidin-3-yl]-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;-   (4S)-7-(3,5-dimethylisoxazol-4-yl)-2-[1-(methylsulfonyl)piperidin-3-yl]-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;-   7-(3,5-Dimethylisoxazol-4-yl)-4-phenyl-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one;-   7-(3,5-Dimethylisoxazol-4-yl)-1-methyl-4-phenyl-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one;-   7-(3,5-Dimethylisoxazol-4-yl)-1-methoxy-4-pyridin-2-yl-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one;-   7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one;-   7-[5-(Hydroxymethyl)-3-methylisoxazol-4-yl]-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;-   7-[5-(Fluoromethyl)-3-methylisoxazol-4-yl]-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;-   3-[7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]pyridine-2-carbonitrile;-   3-[7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]pyridine-2-carboxamide;-   3-[7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]-N-methylpyridine-2-carboxamide;-   3-[7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]-N,N-dimethylpyridine-2-carboxamide;-   4-[2-(Aminomethyl)pyridin-3-yl]-7-(3,5-dimethylisoxazol-4-yl)-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;-   N-({3-[7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]pyridin-2-yl}methyl)acetamide;-   Methyl    3-[7-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]pyridine-2-carboxylate;-   3-[7-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]-N-ethylpyridine-2-carboxamide;-   N-Cyclopropyl-3-[7-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]pyridine-2-carboxamide;-   3-[7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]-N-(2-hydroxyethyl)pyridine-2-carboxamide;-   3-[7-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]-N-(2,2,2-trifluoroethyl)pyridine-2-carboxamide;-   (4S)-9-(Aminomethyl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;-   N-{[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-9-yl]methyl}acetamide;-   N-{[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-9-yl]methyl}-2-phenylacetamide;-   N-{[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-9-yl]methyl}-2-methoxyacetamide;-   N-{[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-9-yl]methyl}methanesulfonamide;-   N-{[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-9-yl]methyl}-N′-isopropylurea;-   2-(Dimethylamino)-N-{[(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-9-yl]methyl}acetamide;-   (4S)-7-(3,5-dimethylisoxazol-4-yl)-9-(1-hydroxyethyl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;-   (3R)-1-[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]-N-isopropylpyrrolidine-3-carboxamide;-   1-[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]-3-methylpyrrolidin-3-ol;-   4-[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]-1,4-diazepane-1-sulfonamide;-   (4S)-2-(4-Acetyl-1,4-diazepan-1-yl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;-   (4S)-7-(3,5-Dimethylisoxazol-4-yl)-2-[4-(methylsulfonyl)-1,4-diazepan-1-yl]-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;-   (4S)-7-(3,5-Dimethylisoxazol-4-yl)-2-piperazin-1-yl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;-   2-{4-[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperazin-1-yl}-N,N-dimethylacetamide;-   2-Cyano-N-{(3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-yl}-N-methylacetamide;-   N-{(3R)-1-[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-yl}morpholine-4-carboxamide;-   7-(3,5-Dimethylisoxazol-4-yl)-2-methyl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;-   Methyl    {(3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-yl}carbamate;-   7-(3,5-Dimethylisoxazol-4-yl)-9-fluoro-N,N-dimethyl-4-pyridin-3-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-amine;-   1-[7-(3,5-Dimethylisoxazol-4-yl)-9-fluoro-4-pyridin-3-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-ol;-   7-(3,5-Dimethylisoxazol-4-yl)-N-ethyl-9-fluoro-4-pyridin-3-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-amine;-   (3R)-1-[7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-3-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-ol;-   1-[7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-3-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]azetidin-3-ol;-   (4S)-7-(3,5-dimethylisoxazol-4-yl)-2-morpholin-4-yl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;-   (4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-2-pyrrolidin-1-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;-   (4S)-7-(3,5-dimethylisoxazol-4-yl)-2-(4-methylpiperazin-1-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;-   (4S)-2-azetidin-1-yl-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;-   1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]azetidin-3-ol;-   4-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]-1-methylpiperazin-2-one;-   ethyl    4-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperazine-1-carboxylate;-   (3R)-1-[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-3-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-ol;-   (3S)-1-[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-3-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-ol;-   1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperidin-4-ol;-   (3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperidin-3-ol;-   (3S)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperidin-3-ol;-   1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]-N,N-dimethylpiperidin-4-amine;-   4-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperazin-2-one;-   (4S)-7-(3,5-dimethylisoxazol-4-yl)-2-[4-(methylsulfonyl)piperazin-1-yl]-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;-   (4S)-7-(3,5-dimethylisoxazol-4-yl)-2-(4-isopropylpiperazin-1-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;-   1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperidine-4-carbonitrile;-   {1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperidin-4-yl}methanol;-   2-{4-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperazin-1-yl}ethanol;-   (4S)-7-(3,5-dimethylisoxazol-4-yl)-2-(4-phenylpiperazin-1-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;-   (4S)-2-(4-benzylpiperazin-1-yl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;-   (3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]-N,N-dimethylpyrrolidin-3-amine;-   (3S)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]-N,N-dimethylpyrrolidin-3-amine;-   (3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]-N-methylpyrrolidin-3-amine;-   (3S)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]-N-methylpyrrolidin-3-amine;-   tert-butyl    {(3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-yl}carbamate;-   tert-butyl    {(3S)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-yl}carbamate;-   (4S)-2-[4-(cyclopropylmethyl)piperazin-1-yl]-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;-   (4S)-7-(3,5-dimethylisoxazol-4-yl)-2-[4-(2-methoxyethyl)piperazin-1-yl]-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;-   2-[[7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl](methyl)amino]ethanol;-   7-(3,5-dimethylisoxazol-4-yl)-N-methyl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-amine;-   7-(3,5-dimethylisoxazol-4-yl)-N,N-dimethyl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-amine;-   1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperidine-4-carboxamide;-   1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]-N-methylpiperidine-4-carboxamide;-   N-{1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperidin-4-yl}acetamide;-   2-{4-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperazin-1-yl}acetamide;-   (4S)-7-(3,5-dimethylisoxazol-4-yl)-2-(4-ethylpiperazin-1-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;-   (4S)-7-(3,5-dimethylisoxazol-4-yl)-2-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;-   (4S)-7-(3,5-dimethylisoxazol-4-yl)-2-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;-   1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]-4-methylpiperidin-4-ol;-   4-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]-3-methylpiperazin-2-one;-   tert-butyl    {1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]azetidin-3-yl}carbamate;-   tert-butyl    4-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]-1,4-diazepane-1-carboxylate;-   2-{[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]amino}ethanol;-   tert-butyl    (2-{[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]amino}ethyl)carbamate;-   N-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]ethane-1,2-diamine;-   N-{(3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-yl}acetamide;-   N-{(3S)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-yl}acetamide;-   (3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-amine;-   (3S)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-amine;-   N-{(3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-yl}-2,2,2-trifluoroacetamide;-   N-{(3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-yl}-2-methoxyacetamide;-   N-{(3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-yl}cyclopropanecarboxamide;-   N-{(3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-yl)}methanesulfonamide;-   N-{(3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-yl}propanamide;-   N-{(3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-yl}-2-methylpropanamide;-   N-{(3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-yl}cyclobutanecarboxamide;-   2-cyano-N-{(3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-yl}acetamide;-   N-{(3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-yl}tetrahydro-2H-pyran-4-carboxamide;-   N-{(3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-yl}ethanesulfonamide;-   N-{(3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-yl}propane-1-sulfonamide;-   N′-{(3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-yl}-N,N-dimethylurea;-   N-{(3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-yl}propane-2-sulfonamide;-   N-{(3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-yl}cyclopropanesulfonamide;-   methyl    {(3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-yl}methylcarbamate;-   N-{(3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-yl}-N-methylmethanesulfonamide;-   N-{(3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-yl}-2-methoxy-N-methylacetamide;-   N-{(3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-yl}-N-methylacetamide;-   (4S)-2-(4-acetylpiperazin-1-yl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;-   (4S)-7-(3,5-dimethylisoxazol-4-yl)-2-(4-propionylpiperazin-1-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;-   (4S)-7-(3,5-dimethylisoxazol-4-yl)-2-[4-(ethylsulfonyl)piperazin-1-yl]-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;-   (4S)-7-(3,5-dimethylisoxazol-4-yl)-2-[4-(2-oxo-2-pyrrolidin-1-ylethyl)piperazin-1-yl]-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;-   4-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperazine-1-sulfonamide;-   1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]azetidin-3-amine;-   N-{1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]azetidin-3-yl}acetamide;-   N-{1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]azetidin-3-yl}propanamide;-   N-{1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]azetidin-3-yl}-2-methylpropanamide;-   N-{1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]azetidin-3-yl}-2-methoxyacetamide;-   N-{1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]azetidin-3-yl}cyclopropanecarboxamide;-   N-{1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]azetidin-3-yl}cyclobutanecarboxamide;-   N-{1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]azetidin-3-yl}methanesulfonamide;-   N-{1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]azetidin-3-yl}ethanesulfonamide;-   N-{1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]azetidin-3-yl}propane-2-sulfonamide;-   N-{1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperidin-4-yl}methanesulfonamide;-   N-{1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperidin-4-yl}-2-methoxyacetamide;-   N-{1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperidin-4-yl}-2,2,2-trifluoroacetamide;-   N-{1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperidin-4-yl}propanamide;-   N-{1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperidin-4-yl}propanamide;-   (4S)-7-(3,5-dimethylisoxazol-4-yl)-2-(4-propionyl-1,4-diazepan-1-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;-   (4S)-7-(3,5-dimethylisoxazol-4-yl)-2-[4-(ethylsulfonyl)-1,4-diazepan-1-yl]-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;-   (3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]-N-methylpyrrolidine-3-carboxamide;-   (3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]-N-ethylpyrrolidine-3-carboxamide;-   (3R)—N-cyclopropyl-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidine-3-carboxamide;-   (4S)-8,9-dichloro-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;-   7-(3,5-Dimethylisoxazol-4-yl)-9-[(isopropylamino)methyl]-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;-   7-(3,5-Dimethylisoxazol-4-yl)-9-(hydroxymethyl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;-   7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine-2(1H)-thione;-   7-(3,5-dimethylisoxazol-4-yl)-9-(1H-pyrazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;-   7-(3,5-dimethylisoxazol-4-yl)-9-(3-methyl-1H-pyrazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;-   7-(3,5-dimethylisoxazol-4-yl)-9-(3,5-dimethyl-1H-pyrazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;-   (4S)-7-(3,5-dimethylisoxazol-4-yl)-9-(6-hydroxypyridin-3-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;-   (4S)-7-(3,5-dimethylisoxazol-4-yl)-9-(2-hydroxypyridin-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;-   (4S)-7-(3,5-dimethylisoxazol-4-yl)-9-(2-hydroxypyridin-3-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;-   9-(anilinomethyl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;-   7-(3,5-dimethylisoxazol-4-yl)-9-{[(4-methoxybenzyl)amino]methyl}-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;-   7-(3,5-dimethylisoxazol-4-yl)-9-(1-hydroxy-2-methylpropyl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;-   7-(3,5-dimethylisoxazol-4-yl)-9-fluoro-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;-   9-chloro-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;-   9-bromo-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;-   7-(3,5-dimethylisoxazol-4-yl)-9-methyl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one;    and-   7-(3,5-dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-9-carbonitrile;

or a pharmaceutically acceptable salt thereof.

When the compounds listed above contain a chiral center, the compoundscan be any of the possible stereoisomers. In compounds with a singlechiral center, the stereochemistry of the chiral center can be (R) or(S). In compounds with two chiral centers, the stereochemistry of thechiral centers can each be independently (R) or (S) so the configurationof the chiral centers can be (R) and (R), (R) and (S); (S) and (R), or(S) and (S). In compounds with three chiral centers, the stereochemistryeach of the three chiral centers can each be independently (R) or (S) sothe configuration of the chiral centers can be (R), (R) and (R); (R),(R) and (S); (R), (S) and (R); (R), (S) and (S); (S), (R) and (R); (S),(R) and (S); (S), (S) and (R); or (S), (S) and (S).

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, can also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention which are, for brevity, described in thecontext of a single embodiment, can also be provided separately or inany suitable subcombination.

The term “substituted” means that an atom or group of atoms formallyreplaces hydrogen as a “substituent” attached to another group. Thehydrogen atom is formally removed and replaced by a substituent. Asingle divalent substituent, e.g., oxo, can replace two hydrogen atoms.The term “optionally substituted” means unsubstituted or substituted.The substituents are independently selected, and substitution may be atany chemically accessible position. It is to be understood thatsubstitution at a given atom is limited by valency. Throughout thedefinitions, the term “C_(n-m)” indicates a range which includes theendpoints, wherein n and m are integers and indicate the number ofcarbons. Examples include C₁₋₄, C₁₋₆, and the like.

The term “n-membered” where n is an integer typically describes thenumber of ring-forming atoms in a moiety where the number ofring-forming atoms is n. For example, piperidinyl is an example of a6-membered heterocycloalkyl ring, pyrazolyl is an example of a5-membered heteroaryl ring, pyridyl is an example of a 6-memberedheteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a10-membered cycloalkyl group.

As used herein, the term “C_(n-m) alkyl,” employed alone or incombination with other terms, refers to a saturated hydrocarbon groupthat may be straight-chain or branched, having n to m carbons. In someembodiments, the alkyl group contains from 1 to 6 carbon atoms or from 1to 4 carbon atoms, or from 1 to 3 carbon atoms. Examples of alkylmoieties include, but are not limited to, chemical groups such asmethyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, and t-butyl.

As used herein, the term “C_(n-m) alkoxy,” employed alone or incombination with other terms, refers to a group of formula —O-alkyl,wherein the alkyl group has n to m carbons. Example alkoxy groupsinclude methoxy, ethoxy, and propoxy (e.g., n-propoxy and isopropoxy).In some embodiments, the alkyl group has 1 to 3 carbon atoms.

As used herein, the term “alkylene,” employed alone or in combinationwith other terms, refers to a divalent alkyl linking group. Examples ofalkylene groups include, but are not limited to, ethan-1, 2-diyl,propan-1, 3-diyl, propan-1, 2-diyl, butan-1,4-diyl, butan-1, 3-diyl,butan-1, 2-diyl, 2-methyl-propan-1, 3-diyl, and the like.

As used herein, “C_(n-m) alkenyl,” employed alone or in combination withother terms, refers to an alkyl group having one or more doublecarbon-carbon bonds and having n to m carbons. In some embodiments, thealkenyl moiety contains 2 to 6 or to 2 to 4 carbon atoms. Examplealkenyl groups include, but are not limited to, ethenyl, n-propenyl,isopropenyl, n-butenyl, sec-butenyl, and the like.

As used herein, “C_(n-m) alkynyl,” employed alone or in combination withother terms, refers to an alkyl group having one or more triplecarbon-carbon bonds and having n to m carbons. Example alkynyl groupsinclude, but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl, andthe like. In some embodiments, the alkynyl moiety contains 2 to 6 or 2to 4 carbon atoms.

As used herein, the term “C_(n-m) alkylamino,” employed alone or incombination with other terms, refers to a group of formula —NH(alkyl),wherein the alkyl group has n to m carbon atoms. In some embodiments,the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

As used herein, the term “di-C_(n-m)-alkylamino,” employed alone or incombination with other terms, refers to a group of formula —N(alkyl)₂,wherein the two alkyl groups each has, independently, n to m carbonatoms. In some embodiments, each alkyl group independently has 1 to 6 or1 to 4 carbon atoms.

As used herein, the term “thio,” employed alone or in combination withother terms, refers to a group of formula —SH.

As used herein, the term “C_(n-m) alkylthio,” employed alone or incombination with other terms, refers to a group of formula —S-alkyl,wherein the alkyl group has n to m carbon atoms. In some embodiments,the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

As used herein, the term “C_(n-m) alkylsulfinyl,” employed alone or incombination with other terms, refers to a group of formula —S(═O)-alkyl,wherein the alkyl group has n to m carbon atoms. In some embodiments,the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

As used herein, the term “C_(n-m) alkylsulfonyl,” employed alone or incombination with other terms, refers to a group of formula—S(═O)₂-alkyl, wherein the alkyl group has n to m carbon atoms. In someembodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

As used herein, the term “amino,” employed alone or in combination withother terms, refers to a group of formula —NH₂.

As used herein, the term “aryl,” employed alone or in combination withother terms, refers to a monocyclic or polycyclic (e.g., having 2, 3 or4 fused rings) aromatic hydrocarbon, such as, but not limited to,phenyl, 1-naphthyl, 2-naphthyl, anthracenyl, phenanthrenyl, and thelike. In some embodiments, aryl is C₆₋₁₀ aryl. In some embodiments, thearyl group is a naphthalene ring or phenyl ring. In some embodiments,the aryl group is phenyl.

As used herein, the term “arylalkyl,” employed alone or in combinationwith other terms, refers to a group of formula -alkylene-aryl. In someembodiments, arylalkyl is C₆₋₁₀ aryl-C₁₋₃ alkyl. In some embodiments,arylalkyl is C₆₋₁₀ aryl-C₁₋₄ alkyl. In some embodiments, arylalkyl isbenzyl.

As used herein, the term “carbonyl,” employed alone or in combinationwith other terms, refers to a —C(═O)— group.

As used herein, the term “carboxy,” employed alone or in combinationwith other terms, refers to a group of formula —C(═O)OH.

As used herein, the term “cycloalkyl,” employed alone or in combinationwith other terms, refers to a non-aromatic cyclic hydrocarbon moiety,which may optionally contain one or more alkenylene groups as part ofthe ring structure. Cycloalkyl groups can include mono- or polycyclic(e.g., having 2, 3 or 4 fused rings) ring systems. Also included in thedefinition of cycloalkyl are moieties that have one or more aromaticrings fused (i.e., having a bond in common with) to the cycloalkyl ring,for example, benzo derivatives of cyclopentane, cyclopentene,cyclohexane, and the like. One or more ring-forming carbon atoms of acycloalkyl group can be oxidized to form carbonyl linkages. In someembodiments, cycloalkyl is C₃₋₇ cycloalkyl, which is monocyclic orbicyclic. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl,cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, andthe like. In some embodiments, the cycloalkyl group is cyclopropyl,cyclobutyl, cyclopentyl, or cyclohexyl.

As used herein, the term “cycloalkylalkyl,” employed alone or incombination with other terms, refers to a group of formula-alkylene-cycloalkyl. In some embodiments, cycloalkylalkyl is C₃₋₇cycloalkyl-C₁₋₃ alkyl, wherein the cycloalkyl portion is monocyclic orbicyclic. In some embodiments, cycloalkylalkyl is C₃₋₇ cycloalkyl-C₁₋₄alkyl, wherein the cycloalkyl portion is monocyclic or bicyclic.

As used herein, “C_(n-m) haloalkoxy,” employed alone or in combinationwith other terms, refers to a group of formula —O-haloalkyl having n tom carbon atoms. An example haloalkoxy group is OCF₃. An additionalexample haloalkoxy group is OCHF₂. In some embodiments, the haloalkoxygroup is fluorinated only. In some embodiments, the alkyl group has 1 to6 or 1 to 4 carbon atoms.

As used herein, the term “halo,” employed alone or in combination withother terms, refers to a halogen atom selected from F, Cl, I or Br. Insome embodiments, “halo” refers to a halogen atom selected from F, Cl,or Br. In some embodiments, exemplary halo groups are F.

As used herein, the term “C_(n-m) haloalkyl,” employed alone or incombination with other terms, refers to an alkyl group having from onehalogen atom to 2s+1 halogen atoms which may be the same or different,where “s” is the number of carbon atoms in the alkyl group, wherein thealkyl group has n to m carbon atoms. In some embodiments, the haloalkylgroup is fluorinated only. In some embodiments, the haloalkyl group isfluoromethyl, difluoromethyl, or trifluoromethyl. In some embodiments,the haloalkyl group is trifluoromethyl. In some embodiments, the alkylgroup has 1 to 6 or 1 to 4 carbon atoms.

As used herein, the term “heteroaryl,” employed alone or in combinationwith other terms, refers to a monocyclic or polycyclic (e.g., having 2,3 or 4 fused rings) aromatic hydrocarbon moiety, having one or moreheteroatom ring members selected from nitrogen, sulfur and oxygen. Insome embodiments, heteroaryl is 5- to 10-membered C₁₋₉ heteroaryl, whichis monocyclic or bicyclic and which has 1, 2, 3, or 4 heteroatom ringmembers independently selected from nitrogen, sulfur and oxygen. Whenthe heteroaryl group contains more than one heteroatom ring member, theheteroatoms may be the same or different. The nitrogen atoms in thering(s) of the heteroaryl group can be oxidized to form N-oxides.Example heteroaryl groups include, but are not limited to, pyridine,pyrimidine, pyrazine, pyridazine, pyrrole, pyrazole, azolyl, oxazole,thiazole, imidazole, furan, thiophene, quinoline, isoquinoline, indole,benzothiophene, benzofuran, benzisoxazole, imidazo[1,2-b]thiazole,purine, or the like.

A five-membered ring heteroaryl is a heteroaryl group having five ringatoms comprising carbon and one or more (e.g., 1, 2, or 3) ring atomsindependently selected from N, O, and S. Exemplary five-membered ringheteroaryls are thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl,oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl,tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl,1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl,1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl.

A six-membered ring heteroaryl is a heteroaryl with a ring having sixring atoms wherein one or more (e.g., 1, 2, or 3) ring atoms areindependently selected from N, O, and S. Exemplary six-membered ringheteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl andpyridazinyl.

As used herein, the term “heteroarylalkyl,” employed alone or incombination with other terms, refers to a group of formula-alkylene-heteroaryl. In some embodiments, heteroarylalkyl is C₁₋₉heteroaryl-C₁₋₃ alkyl, wherein the heteroaryl portion is monocyclic orbicyclic and has 1, 2, 3, or 4 heteroatom ring members independentlyselected from nitrogen, sulfur and oxygen. In some embodiments,heteroarylalkyl is C₁₋₉ heteroaryl-C₁₋₄ alkyl, wherein the heteroarylportion is monocyclic or bicyclic and has 1, 2, 3, or 4 heteroatom ringmembers independently selected from nitrogen, sulfur and oxygen.

As used herein, the term “heterocycloalkyl,” employed alone or incombination with other terms, refers to non-aromatic ring system, whichmay optionally contain one or more alkenylene or alkynylene groups aspart of the ring structure, and which has at least one heteroatom ringmember independently selected from nitrogen, sulfur and oxygen. When theheterocycloalkyl groups contains more than one heteroatom, theheteroatoms may be the same or different. Heterocycloalkyl groups caninclude mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) ringsystems, including spiro systems. Also included in the definition ofheterocycloalkyl are moieties that have one or more aromatic rings fused(i.e., having a bond in common with) to the non-aromatic ring, forexample, 1,2,3,4-tetrahydro-quinoline, dihydrobenzofuran and the like.The carbon atoms or heteroatoms in the ring(s) of the heterocycloalkylgroup can be oxidized to form a carbonyl, or sulfonyl group (or otheroxidized linkage) or a nitrogen atom can be quaternized. In someembodiments, heterocycloalkyl is 5- to 10-membered C₂₋₉heterocycloalkyl, which is monocyclic or bicyclic and which has 1, 2, 3,or 4 heteroatom ring members independently selected from nitrogen,sulfur and oxygen. Examples of heterocycloalkyl groups include 1, 2, 3,4-tetrahydro-quinoline, dihydrobenzofuran, azetidine, azepane,pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, andpyran.

As used herein, the term “heterocycloalkylalkyl,” employed alone or incombination with other terms, refers to a group of formula-alkylene-heterocycloalkyl. In some embodiments, heterocycloalkylalkylis C₂₋₉ heterocycloalkyl-C₁₋₃ alkyl, wherein the heterocycloalkylportion is monocyclic or bicyclic and has 1, 2, 3, or 4 heteroatom ringmembers independently selected from nitrogen, sulfur and oxygen. In someembodiments, heterocycloalkylalkyl is C₂₋₉ heterocycloalkyl-C₁₋₄ alkyl,wherein the heterocycloalkyl portion is monocyclic or bicyclic and has1, 2, 3, or 4 heteroatom ring members independently selected fromnitrogen, sulfur and oxygen.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereoisomers, are intended unless otherwise indicated. Compounds ofthe present invention that contain asymmetrically substituted carbonatoms can be isolated in optically active or racemic forms. Methods onhow to prepare optically active forms from optically inactive startingmaterials are known in the art, such as by resolution of racemicmixtures or by stereoselective synthesis. Many geometric isomers ofolefins, C═N double bonds, and the like can also be present in thecompounds described herein, and all such stable isomers are contemplatedin the present invention. Cis and trans geometric isomers of thecompounds of the present invention are described and may be isolated asa mixture of isomers or as separated isomeric forms.

Resolution of racemic mixtures of compounds can be carried out by any ofnumerous methods known in the art. An example method includes fractionalrecrystallization using a chiral resolving acid which is an opticallyactive, salt-forming organic acid. Suitable resolving agents forfractional recrystallization methods are, for example, optically activeacids, such as the D and L forms of tartaric acid, diacetyltartaricacid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid orthe various optically active camphorsulfonic acids such asβ-camphorsulfonic acid. Other resolving agents suitable for fractionalcrystallization methods include stereoisomerically pure forms ofα-methylbenzylamine (e.g., S and R forms, or diastereoisomerically pureforms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine,cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

Resolution of racemic mixtures can also be carried out by elution on acolumn packed with an optically active resolving agent (e.g.,dinitrobenzoylphenylglycine). Suitable elution solvent composition canbe determined by one skilled in the art.

Compounds of the invention also include tautomeric forms. Tautomericforms result from the swapping of a single bond with an adjacent doublebond together with the concomitant migration of a proton. Tautomericforms include prototropic tautomers which are isomeric protonationstates having the same empirical formula and total charge. Exampleprototropic tautomers include ketone-enol pairs, amide-imidic acidpairs, lactam-lactim pairs, amide-imidic acid pairs, enamine-iminepairs, and annular forms where a proton can occupy two or more positionsof a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H-and 4H-1, 2, 4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole.Tautomeric forms can be in equilibrium or sterically locked into oneform by appropriate substitution.

Compounds of the invention can also include all isotopes of atomsoccurring in the intermediates or final compounds. Isotopes includethose atoms having the same atomic number but different mass numbers.

The term, “compound,” as used herein is meant to include allstereoisomers, geometric isomers, tautomers, and isotopes of thestructures depicted. Compounds herein identified by name or structure asone particular tautomeric form are intended to include other tautomericforms unless otherwise specified (e.g., in the case of purine rings,unless otherwise indicated, when the compound name or structure has the9H tautomer, it is understood that the 7H tautomer is also encompassed).

All compounds, and pharmaceutically acceptable salts thereof, can befound together with other substances such as water and solvents (e.g.,hydrates and solvates) or can be isolated.

In some embodiments, the compounds of the invention, or salts thereof,are substantially isolated. By “substantially isolated” is meant thatthe compound is at least partially or substantially separated from theenvironment in which it was formed or detected. Partial separation caninclude, for example, a composition enriched in the compounds of theinvention. Substantial separation can include compositions containing atleast about 50%, at least about 60%, at least about 70%, at least about80%, at least about 90%, at least about 95%, at least about 97%, or atleast about 99% by weight of the compounds of the invention, or saltthereof. Methods for isolating compounds and their salts are routine inthe art.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The expressions, “ambient temperature” and “room temperature,” as usedherein, are understood in the art, and refer generally to a temperature,e.g., a reaction temperature, that is about the temperature of the roomin which the reaction is carried out, for example, a temperature fromabout 20° C. to about 30° C.

The present invention also includes pharmaceutically acceptable salts ofthe compounds described herein. As used herein, “pharmaceuticallyacceptable salts” refers to derivatives of the disclosed compoundswherein the parent compound is modified by converting an existing acidor base moiety to its salt form. Examples of pharmaceutically acceptablesalts include, but are not limited to, mineral or organic acid salts ofbasic residues such as amines; alkali or organic salts of acidicresidues such as carboxylic acids; and the like. The pharmaceuticallyacceptable salts of the present invention include the conventionalnon-toxic salts of the parent compound formed, for example, fromnon-toxic inorganic or organic acids. The pharmaceutically acceptablesalts of the present invention can be synthesized from the parentcompound which contains a basic or acidic moiety by conventionalchemical methods. Generally, such salts can be prepared by reacting thefree acid or base forms of these compounds with a stoichiometric amountof the appropriate base or acid in water or in an organic solvent, or ina mixture of the two; generally, non-aqueous media like ether, ethylacetate, alcohols (e.g., methanol, ethanol, iso-propanol, or butanol) oracetonitrile (MeCN) are preferred. Lists of suitable salts are found inRemington's Pharmaceutical Sciences, 17^(th) Ed., (Mack PublishingCompany, Easton, 1985), p. 1418, Berge et al., J. Pharm. Sci., 1977,66(1), 1-19, and in Stahl et al., Handbook of Pharmaceutical Salts:Properties, Selection, and Use, (Wiley, 2002). In some embodiments, thecompounds described herein include the N-oxide forms.

The following abbreviations may be used herein: AcOH (acetic acid); Ac₂O(acetic anhydride); aq. (aqueous); atm. (atmosphere(s)); Boc(t-butoxycarbonyl); br (broad); Cbz (carboxybenzyl); calc. (calculated);d (doublet); dd (doublet of doublets); DCM (dichloromethane); DEAD(diethyl azodicarboxylate); DIAD (N,N′-diisopropyl azidodicarboxylate);DIPEA (N,N-diisopropylethylamine); DMF (N,N-dimethylformamide); Et(ethyl); EtOAc (ethyl acetate); g (gram(s)); h (hour(s)); HATU(N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate); HCl (hydrochloric acid); HPLC (high performanceliquid chromatography); Hz (hertz); J (coupling constant); LCMS (liquidchromatography-mass spectrometry); m (multiplet); M (molar); mCPBA(3-chloroperoxybenzoic acid); MgSO₄ (magnesium sulfate); MS (Massspectrometry); Me (methyl); MeCN (acetonitrile); MeOH (methanol); mg(milligram(s)); min. (minutes(s)); mL (milliliter(s)); mmol(millimole(s)); N (normal); NaHCO₃ (sodium bicarbonate); NaOH (sodiumhydroxide); Na₂SO₄ (sodium sulfate); NH₄Cl (ammonium chloride); NH₄OH(ammonium hydroxide); nM (nanomolar); NMR (nuclear magnetic resonancespectroscopy); OTf (trifluoromethanesulfonate); Pd (palladium); Ph(phenyl); pM (picomolar); POCl₃ (phosphoryl chloride); RP-HPLC (reversephase high performance liquid chromatography); s (singlet); t (tripletor tertiary); TBS (tert-butyldimethylsilyl); tert (tertiary); tt(triplet of triplets); t-Bu (tert-butyl); TFA (trifluoroacetic acid);THF (tetrahydrofuran); μg (microgram(s)); μL (microliter(s)); μM(micromolar); wt % (weight percent).

II. Synthesis

Compounds of the invention, including salts thereof, can be preparedusing known organic synthesis techniques and can be synthesizedaccording to any of numerous possible synthetic routes.

The reactions for preparing compounds of the invention can be carriedout in suitable solvents which can be readily selected by one of skillin the art of organic synthesis. Suitable solvents can be substantiallynon-reactive with the starting materials (reactants), the intermediates,or products at the temperatures at which the reactions are carried out,e.g., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected by the skilled artisan.

Preparation of compounds of the invention can involve the protection anddeprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups, can bereadily determined by one skilled in the art. The chemistry ofprotecting groups is described, e.g., in Kocienski, Protecting Groups,(Thieme, 2007); Robertson, Protecting Group Chemistry, (OxfordUniversity Press, 2000); Smith et al., March's Advanced OrganicChemistry: Reactions, Mechanisms, and Structure, 6^(th) Ed. (Wiley,2007); Peturssion et al., “Protecting Groups in Carbohydrate Chemistry,”J Chem. Educ., 1997, 74(11), 1297; and Wuts et al., Protective Groups inOrganic Synthesis, 4th Ed., (Wiley, 2006).

Reactions can be monitored according to any suitable method known in theart. For example, product formation can be monitored by spectroscopicmeans, such as nuclear magnetic resonance spectroscopy (e.g., ¹H or¹³C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), massspectrometry, or by chromatographic methods such as high performanceliquid chromatography (HPLC), liquid chromatography-mass spectroscopy(LCMS), or thin layer chromatography (TLC). Compounds can be purified bythose skilled in the art by a variety of methods, including highperformance liquid chromatography (HPLC) (“Preparative LCMSPurification: Improved Compound Specific Method Optimization” Karl F.Blom, Brian Glass, Richard Sparks, Andrew P. Combs J. Combi. Chem. 2004,6(6), 874-883) and normal phase silica chromatography.

Compounds of Formula (I) can be formed as shown in Scheme I. The thiols(L=S) or phenols (L=O) (i) can be alkylated using standard alkylatingconditions (Cy³COC(R¹R²)—X (ii), X=leaving group, such as halo (Br, Cl,I or mesylate) or Mitsunobu conditions (e.g., Cy³COC(R¹R²)—X, where X═OH(ii), DEAD, Ph₃P) to afford thioether or ether derivatives (iii),respectively. Cyclization in situ or upon heating can afford imine (iv)which upon treatment with a Grignard reagent of formula R⁴—MgX¹(X¹=halo) and reduction of the nitro group (e.g., H₂ Pd/C or Fe) to givean amine (v). Compounds (v) can either be reacted withcarbonyldiamidazole or phosgene to form an urea and then halogenatedwith N-chlorosuccinimide, N-bromosuccinimide or N-iodosuccinimide togive tricyclic halide (vi) where X═Cl, Br or I or halogenated first andthen reacted with carbonyldiamidazole or phosgene to form an urea andgive tricyclic halide (vi). Compound (vi) can be alkylated (e.g., R⁶—X,where X=halo (X═Br, Cl, or I) and a base, such as triethylamine, NaH orNa₂CO₃; or under Mitsunobu conditions) to afford the tetrasubstitutedurea (vii). Finally, the halo group of (vii) can be coupled to M-Cy¹,where M is a boronic acid, boronic ester or an appropriately substitutedmetal (e.g., Cy¹-M is Cy¹-B(OH)₂, Cy¹-Sn(Bu)₄, or Zn-Cy¹), understandard Suzuki conditions or standard Stille conditions (e.g., in thepresence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0) and a base (e.g., a bicarbonateor carbonate base) or standard Negishi conditions (e.g., in the presenceof a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0), to give a derivative ofFormula (I) (viii) wherein R⁵ is ═O. Alternatively, M-Cy¹ can be anamine containing heterocycle (where M is H and is attached to the aminenitrogen of the heterocycle Cy¹) with coupling to compound (vii) beingperformed by heating with a base or under Buchwald conditions (e.g., inthe presence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0) and a base (e.g., an alkoxidebase)) to give a derivative of Formula (I) (viii). Alternatively, urea(vi) can be coupled to M-Cy¹, where M is a boronic acid, boronic esteror an appropriately substituted metal (e.g., Cy¹-M is Cy¹-B(OH)₂,Cy¹-Sn(Bu)₄, or Zn-Cy¹), under standard Suzuki conditions or standardStille conditions (e.g., in the presence of a palladium(0) catalyst,such as tetrakis(triphenylphosphine)palladium(0) and a base (e.g., abicarbonate or carbonate base) or standard Negishi conditions (e.g., inthe presence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0), to give a derivative ofFormula (I) (ix) which can be alkylated (e.g., R⁶—X, where X=halo (X═Br,Cl, or I) and a base, such as triethylamine, NaH or Na₂CO₃; or underMitsunobu conditions) to afford the tetrasubstituted urea of Formula (I)(viii). Alternatively, urea (vi) can be converted to the2-halo-imidazole, such as Cl upon treatment with POCl₃, and then treatedwith an amine (HNRR) to give benzoimidazole (x) where R⁵═NRR.Benzoimidazole (x) can then be coupled to M-Cy¹, where M is a boronicacid, boronic ester or an appropriately substituted metal (e.g., Cy¹-Mis Cy¹-B(OH)₂, Cy¹-Sn(Bu)₄, or Zn-Cy¹), under standard Suzuki conditionsor standard Stille conditions (e.g., in the presence of a palladium(0)catalyst, such as tetrakis(triphenylphosphine)palladium(0) and a base(e.g., a bicarbonate or carbonate base) or standard Negishi conditions(e.g., in the presence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0), to give a derivative ofFormula (I) (xi). M-Cy¹ can be an amine containing heterocycle (where Mis H and is attached to the amine nitrogen of the heterocycle Cy¹) withcoupling to compound (x) being performed by heating with a base or underBuchwald conditions (e.g., in the presence of a palladium(0) catalyst,such as tetrakis(triphenylphosphine)palladium(0) and a base (e.g., analkoxide base)) to give a derivative of Formula (I) (xi). Alternatively,urea (ix) can be converted to the 2-halo-imidazole, such as Cl upontreatment with POCl₃, and then treated with an amine (HNRR) to givebenzimidazole (xi) where R⁵═NRR or the chloride derivative can becoupled to M-R⁵, where M is a boronic acid, boronic ester or anappropriately substituted metal (e.g., R⁵-M is R⁵—B(OH)₂, R⁵—Sn(Bu)₄, orZn—R⁵), under standard Suzuki conditions or standard Stille conditions(e.g., in the presence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0) and a base (e.g., a bicarbonateor carbonate base) or standard Negishi conditions (e.g., in the presenceof a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0), to give a derivative ofFormula (I) (xi). M-Cy¹ can be an amine containing heterocycle (where Mis H and is attached to the amine nitrogen of the heterocycle Cy¹) withcoupling to the halide of (ix) being performed by heating with a base orunder Buchwald conditions (e.g., in the presence of a palladium(0)catalyst, such as tetrakis(triphenylphosphine)palladium(0) and a base(e.g., an alkoxide base)) to give a derivative of Formula (I) (xi).Amino compound (v) can either be treated with an ortho-ester, such asR⁵C(OEt)₃, or an aldehyde R⁵CHO and NaHSO₃ to give a benzimidazole whichcan be halogenated with N-chlorosuccinimide, N-bromosuccinimide orN-iodosuccinimide to give halo-benzimidazole (x), where X═Cl, Br, or I,or these two steps can be run in the opposite order to give the samebenzimidazole (x) which can be further converted to compounds of Formula(I) (xi) as previously described above.

Compounds of Formula (I) can be formed as shown in Scheme II. Thenitro-halide (i) can be reacted with an amine, such as HNR⁶, to give anamino derivative which can be alkylated with (Cy³COC(R¹R²)—X (ii) usingstandard alkylating conditions, X=leaving group, such as halo (Br, Cl,I) or mesylate) or Mitsunobu conditions (e.g., Cy³COC(R¹R²)—X, whereX═OH (ii), DEAD, Ph₃P) to afford thioether or ether derivatives (iii),respectively. Reduction of the nitro group of (iii) under standardconditions (e.g., Fe or Zn) can give the amino compound which cancyclize in situ or upon heating to afford an imine which upon treatmentwith a Grignard reagent of formula R⁴—MgX¹ (X¹=halo) to give an amine(iv) or (iii) can be reduced with H₂ over Pd/C to give amine (iv) whereR⁴═H. Compounds (iv) can either be reacted with carbonyldiimidazole orphosgene to form an urea and then halogenated with N-chlorosuccinimide,N-bromosuccinimide or N-iodosuccinimide to give tricyclic halide (v)where X═Cl, Br or I or halogenated first and then reacted withcarbonyldiimidazole or phosgene to form an urea and give tricyclichalide (v). Finally, the halo group of (v) can be coupled to M-Cy¹,where M is a boronic acid, boronic ester or an appropriately substitutedmetal (e.g., Cy¹-M is Cy¹-B(OH)₂, Cy¹-Sn(Bu)₄, or Zn-Cy¹), understandard Suzuki conditions or standard Stille conditions (e.g., in thepresence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0) and a base (e.g., a bicarbonateor carbonate base) or standard Negishi conditions (e.g., in the presenceof a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0), to give a derivative ofFormula (I) (vi). M-Cy¹ can be an amine containing heterocycle (where Mis H and is attached to the amine nitrogen of the heterocycle Cy¹) withcoupling to compound (v) being performed by heating with a base or underBuchwald conditions (e.g., in the presence of a palladium(0) catalyst,such as tetrakis(triphenylphosphine)palladium(0) and a base (e.g., analkoxide base)) to give a derivative of Formula (I) (vi).

Compounds of Formula (I) can be formed as shown in Scheme III. Thenitro-halide (i) can be reacted with an amine of formulaHO₂CC(R¹R²)C(Cy³R⁴)—NH₂, to give a carboxylic acid derivative (iii).Conversion of the carboxylic acid (iii) to an acyl-halide, such asacyl-chloride by treating with oxalyl-chloride, can affect aFriedel-Crafts intramolecular cyclization to give ketone (iv). Reductionof the ketone group and nitro group of (iv) under standard conditions(e.g., H₂ over Pd/C or a Wolff-Kishner reaction (NH₂NH₂, KOH) followedby reduction of the nitro group with Fe) can give the diamine derivative(v). Diamine (v) can then be converted to compounds of Formula (I)(where L=CH₂) by similar methods for diamine (v) shown in Scheme I.

Compounds of Formula (I) can be formed as shown in Scheme IV. Compounds(i) can be halogenated with N-chlorosuccinimide, N-bromosuccinimide orN-iodosuccinimide to give tricyclic halide (v) where X═Cl, Br or I andthe halo group of (ii) can be coupled to M-R⁷, where M is a boronicacid, boronic ester or an appropriately substituted metal (e.g., R⁷-M isR⁷—B(OH)₂, R⁷—Sn(Bu)₄, or Zn—R⁷), under standard Suzuki conditions orstandard Stille conditions (e.g., in the presence of a palladium(0)catalyst, such as tetrakis(triphenylphosphine)palladium(0) and a base(e.g., a bicarbonate or carbonate base) or standard Negishi conditions(e.g., in the presence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0), to give a derivative ofFormula (I) (vi). M-R⁷ can be an amine containing heterocycle (where Mis H and is attached to the amine nitrogen of the heterocycle R⁷) withcoupling to compound (ii) being performed by heating with a base orunder Buchwald conditions (e.g., in the presence of a palladium(0)catalyst, such as tetrakis(triphenylphosphine)palladium(0) and a base(e.g., an alkoxide base)) to give a derivative of Formula (I) (iii).

Compounds of Formula (I) can be formed as shown in Scheme V. Thenitro-aniline (i) can be reacted with an aldehyde of formulaOHCC(R¹)=CHCy³ (ii), to give quinolone derivatives (iii). Reduction ofthe quinoline group and nitro group of (iii) under standard conditions(e.g., H₂ over Pd/C can give the diamine derivative (iv). Diamine (iv)can then be converted to compounds of Formula (I) (where L=CH₂) bysimilar methods for diamine (v) shown in Scheme I.

Compounds of Formula (I) can be formed as shown in Scheme VI. Thesulfide (i) can be reacted with an oxidant, such as mCPBA or H₂O₂ ordioxirane, to give the sulfoxide (ii) which can be further oxidized withan oxidant, such as mCPBA or H₂O₂ or dioxirane, to give the sulfone(iii).

Halo-ketones intermediate (ii) of Scheme I and Scheme II can besynthesized as shown in Scheme VII. The carboxylic acid (i) can beactivated with a coupling agent (e.g., HBTU, HATU or EDC) and thenreacted with N, O-dimethylhydroxylamine to give anN-methoxy-N-methylcarboxamide derivative (ii). Amide (ii) may then bereacted with a Grignard reagent of formula R¹R²—CH—MgX¹ (X¹=halo) togive a ketone (iii) which can be halogenated with Br₂ or NXS (X═Br, Clor I) to give halo-ketone (iv). The halo-ketone (iv) can be transformedusing similar methods as shown in Scheme I and Scheme II to affordcompounds of Formula (I).

Compounds of Formula (I) can be formed as shown in Scheme VIII.2-Bromoquinoline (i) can be coupled to M-Cy³, where M is a boronic acid,boronic ester or an appropriately substituted metal (e.g., Cy¹-M isCy¹-B(OH)₂, Cy¹-Sn(Bu)₄, or Zn-Cy¹), under standard Suzuki conditions orstandard Stille conditions (e.g., in the presence of a palladium(0)catalyst, such as tetrakis(triphenylphosphine)palladium(0) and a base(e.g., a bicarbonate or carbonate base) or standard Negishi conditions(e.g., in the presence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0), to give compound (ii).Compound (ii) can be reduced (eg. borane/pyridine or1,4-dihydro-3,5-dicarbethoxy-2,6-dimethylpyridine/diphenyl hydrogenphosphate) to give compound (iii). Compound (iii) can be converted to(iv) using triphosgene/methoxylamine or 4-nitrophenyl methoxycarbamate.Cyclization of (iv) can be accomplished with[I,I-bis(trifluoroacetoxy)iodo]benzene to give (v). The methoxy group of(v) can be removed by hydrogenation (Pd/C) to give (vi). Compound (vi)can be halogenated with N-chlorosuccinimide, N-bromosuccinimide orN-iodosuccinimide to give tricyclic halide (vii) where X═Cl, Br or I.Finally, the halo group of (vii) can be coupled to M-Cy¹, where M is aboronic acid, boronic ester or an appropriately substituted metal (e.g.,Cy¹-M is Cy¹-B(OH)₂, Cy¹-Sn(Bu)₄, or Zn-Cy¹), under standard Suzukiconditions or standard Stille conditions (e.g., in the presence of apalladium(0) catalyst, such as tetrakis(triphenylphosphine)palladium(0)and a base (e.g., a bicarbonate or carbonate base) or standard Negishiconditions (e.g., in the presence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0), to give a derivative ofFormula (I) (viii).

For the synthesis of particular compounds, the general schemes describedabove can be modified. For example, the products or intermediates can bemodified to introduce particular functional groups. Alternatively, thesubstituents can be modified at any step of the overall synthesis bymethods know to one skilled in the art, e.g., as described by Larock,Comprehensive Organic Transformations: A Guide to Functional GroupPreparations (Wiley, 1999); and Katritzky et al. (Ed.), ComprehensiveOrganic Functional Group Transformations (Pergamon Press 1996).

Starting materials, reagents and intermediates whose synthesis is notdescribed herein are either commercially available, known in theliterature, or may be prepared by methods known to one skilled in theart.

It will be appreciated by one skilled in the art that the processesdescribed are not the exclusive means by which compounds of theinvention may be synthesized and that a broad repertoire of syntheticorganic reactions is available to be potentially employed insynthesizing compounds of the invention. The person skilled in the artknows how to select and implement appropriate synthetic routes. Suitablesynthetic methods of starting materials, intermediates and products maybe identified by reference to the literature, including referencesources such as: Advances in Heterocyclic Chemistry, Vols. 1-107(Elsevier, 1963-2012); Journal of Heterocyclic Chemistry Vols. 1-49(Journal of Heterocyclic Chemistry, 1964-2012); Carreira, et al. (Ed.)Science of Synthesis, Vols. 1-48 (2001-2010) and Knowledge UpdatesKU2010/1-4; 2011/1-4; 2012/1-2 (Thieme, 2001-2012); Katritzky, et al.(Ed.) Comprehensive Organic Functional Group Transformations, (PergamonPress, 1996); Katritzky et al. (Ed.); Comprehensive Organic FunctionalGroup Transformations II (Elsevier, 2^(nd) Edition, 2004); Katritzky etal. (Ed.), Comprehensive Heterocyclic Chemistry (Pergamon Press, 1984);Katritzky et al., Comprehensive Heterocyclic Chemistry II, (PergamonPress, 1996); Smith et al., March's Advanced Organic Chemistry:Reactions, Mechanisms, and Structure, 6^(th) Ed. (Wiley, 2007); Trost etal. (Ed.), Comprehensive Organic Synthesis (Pergamon Press, 1991).

III. Uses of the Compounds

Compounds of the invention are BET protein inhibitors and, thus, areuseful in treating diseases and disorders associated with activity ofBET proteins. For the uses described herein, any of the compounds of theinvention, including any of the embodiments thereof, may be used.

The compounds of Formula (I) can inhibit one or more of BET proteinsBRD2, BRD3, BRD4, and BRD-t. In some embodiments, the compounds of theinvention selectively inhibit one or more BET proteins over another.“Selective” means that the compound binds to or inhibits a BET proteinwith greater affinity or potency, respectively, compared to a reference,such as another BET protein. For example, the compounds can be selectivefor BRD2 over BRD3, BRD4 and BRD-t, selective for BRD3 over BRD2, BRD4and BRD-t, selective for BRD4 over BRD2, BRD3 and BRD-t, or selectivefor BRD-t over BRD2, BRD3 and BRD4. In some embodiments, the compoundsinhibit two or more of the BET proteins, or all of the BET proteins. Ingeneral, selectivity can be at least about 5-fold, at least about10-fold, at least about 20-fold, at least about 50-fold, at least about100-fold, at least about 200-fold, at least about 500-fold or at leastabout 1000-fold.

The compounds of Formula (I) are therefore useful for treating BETprotein mediated disorders. The term “BET-mediated” refers to anydisease or condition in which one or more of the BET proteins, such asBRD2, BRD3, BRD4 and/or BRD-t, or a mutant thereof, plays a role, orwhere the disease or condition is associated with expression or activityof one or more of the BET proteins. The compounds of the invention cantherefore be used to treat or lessen the severity of diseases andconditions where BET proteins, such as BRD2, BRD3, BRD4, and/or BRD-t,or a mutant thereof, are known to play a role.

Diseases and conditions treatable using the compounds of Formula (I)include cancer and other proliferative disorders, autoimmune disease,chronic inflammatory diseases, acute inflammatory diseases, sepsis, andviral infection. The diseases can be treated by administering to anindividual (e.g., a patient) in need of the treatment a therapeuticallyeffective amount or dose of a compound of Formula (I), or any of theembodiments thereof, or a pharmaceutical composition thereof. Thepresent disclosure also provides a compound of Formula (I), or any ofthe embodiments thereof, or a pharmaceutical composition thereof, foruse in treating a BET-mediated disease or disorder. Also provided is theuse of a compound of Formula (I), or any of the embodiments thereof, ora pharmaceutical composition thereof, in the manufacture of a medicamentfor treating a BET-mediated disease or disorder.

Diseases that can be treated with the compounds of Formula (I) includecancers. The cancers can include adrenal cancer, acinic cell carcinoma,acoustic neuroma, acral lentiginous melanoma, acrospiroma, acuteeosinophilic leukemia, acute erythroid leukemia, acute lymphoblasticleukemia, acute megakaryoblastic leukemia, acute monocytic leukemia,acute promyelocytic leukemia, adenocarcinoma, adenoid cystic carcinoma,adenoma, adenomatoid odontogenic tumor, adenosquamous carcinoma, adiposetissue neoplasm, adrenocortical carcinoma, adult T-cellleukemia/lymphoma, aggressive NK-cell leukemia, AIDS-related lymphoma,alveolar rhabdomyosarcoma, alveolar soft part sarcoma, ameloblasticfibroma, anaplastic large cell lymphoma, anaplastic thyroid cancer,angioimmunoblastic T-cell lymphoma, angiomyolipoma, angiosarcoma,astrocytoma, atypical teratoid rhabdoid tumor, B-cell chroniclymphocytic leukemia, B-cell prolymphocytic leukemia, B-cell lymphoma,basal cell carcinoma, biliary tract cancer, bladder cancer, blastoma,bone cancer, Brenner tumor, Brown tumor, Burkitt's lymphoma, breastcancer, brain cancer, carcinoma, carcinoma in situ, carcinosarcoma,cartilage tumor, cementoma, myeloid sarcoma, chondroma, chordoma,choriocarcinoma, choroid plexus papilloma, clear-cell sarcoma of thekidney, craniopharyngioma, cutaneous T-cell lymphoma, cervical cancer,colorectal cancer, Degos disease, desmoplastic small round cell tumor,diffuse large B-cell lymphoma, dysembryoplastic neuroepithelial tumor,dysgerminoma, embryonal carcinoma, endocrine gland neoplasm, endodermalsinus tumor, enteropathy-associated T-cell lymphoma, esophageal cancer,fetus in fetu, fibroma, fibrosarcoma, follicular lymphoma, follicularthyroid cancer, ganglioneuroma, gastrointestinal cancer, germ celltumor, gestational choriocarcinoma, giant cell fibroblastoma, giant celltumor of the bone, glial tumor, glioblastoma multiforme, glioma,gliomatosis cerebri, glucagonoma, gonadoblastoma, granulosa cell tumor,gynandroblastoma, gallbladder cancer, gastric cancer, hairy cellleukemia, hemangioblastoma, head and neck cancer, hemangiopericytoma,hematological malignancy, hepatoblastoma, hepatosplenic T-cell lymphoma,Hodgkin's lymphoma, non-Hodgkin's lymphoma, invasive lobular carcinoma,intestinal cancer, kidney cancer, laryngeal cancer, lentigo maligna,lethal midline carcinoma, leukemia, leydig cell tumor, liposarcoma, lungcancer, lymphangioma, lymphangiosarcoma, lymphoepithelioma, lymphoma,acute lymphocytic leukemia, acute myelogenous leukemia, chroniclymphocytic leukemia, liver cancer, small cell lung cancer, non-smallcell lung cancer, MALT lymphoma, malignant fibrous histiocytoma,malignant peripheral nerve sheath tumor, malignant triton tumor, mantlecell lymphoma, marginal zone B-cell lymphoma, mast cell leukemia,mediastinal germ cell tumor, medullary carcinoma of the breast,medullary thyroid cancer, medulloblastoma, melanoma, meningioma, merkelcell cancer, mesothelioma, metastatic urothelial carcinoma, mixedMullerian tumor, mucinous tumor, multiple myeloma, muscle tissueneoplasm, mycosis fungoides, myxoid liposarcoma, myxoma, myxosarcoma,nasopharyngeal carcinoma, neurinoma, neuroblastoma, neurofibroma,neuroma, nodular melanoma, ocular cancer, oligoastrocytoma,oligodendroglioma, oncocytoma, optic nerve sheath meningioma, opticnerve tumor, oral cancer, osteosarcoma, ovarian cancer, Pancoast tumor,papillary thyroid cancer, paraganglioma, pinealoblastoma, pineocytoma,pituicytoma, pituitary adenoma, pituitary tumor, plasmacytoma,polyembryoma, precursor T-lymphoblastic lymphoma, primary centralnervous system lymphoma, primary effusion lymphoma, primary peritonealcancer, prostate cancer, pancreatic cancer, pharyngeal cancer,pseudomyxoma peritonei, renal cell carcinoma, renal medullary carcinoma,retinoblastoma, rhabdomyoma, rhabdomyosarcoma, Richter's transformation,rectal cancer, sarcoma, Schwannomatosis, seminoma, Sertoli cell tumor,sex cord-gonadal stromal tumor, signet ring cell carcinoma, skin cancer,small blue round cell tumors, small cell carcinoma, soft tissue sarcoma,somatostatinoma, soot wart, spinal tumor, splenic marginal zonelymphoma, squamous cell carcinoma, synovial sarcoma, Sezary's disease,small intestine cancer, squamous carcinoma, stomach cancer, T-celllymphoma, testicular cancer, thecoma, thyroid cancer, transitional cellcarcinoma, throat cancer, urachal cancer, urogenital cancer, urothelialcarcinoma, uveal melanoma, uterine cancer, verrucous carcinoma, visualpathway glioma, vulvar cancer, vaginal cancer, Waldenstrom'smacroglobulinemia, Warthin's tumor, and Wilms' tumor. In someembodiments, the cancer can be adenocarcinoma, adult T-cellleukemia/lymphoma, bladder cancer, blastoma, bone cancer, breast cancer,brain cancer, carcinoma, myeloid sarcoma, cervical cancer, colorectalcancer, esophageal cancer, gastrointestinal cancer, glioblastomamultiforme, glioma, gallbladder cancer, gastric cancer, head and neckcancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, intestinal cancer,kidney cancer, laryngeal cancer, leukemia, lung cancer, lymphoma, livercancer, small cell lung cancer, non-small cell lung cancer,mesothelioma, multiple myeloma, ocular cancer, optic nerve tumor, oralcancer, ovarian cancer, pituitary tumor, primary central nervous systemlymphoma, prostate cancer, pancreatic cancer, pharyngeal cancer, renalcell carcinoma, rectal cancer, sarcoma, skin cancer, spinal tumor, smallintestine cancer, stomach cancer, T-cell lymphoma, testicular cancer,thyroid cancer, throat cancer, urogenital cancer, urothelial carcinoma,uterine cancer, vaginal cancer, or Wilms' tumor.

The diseases treatable using the compounds of Formula (I) also includeMYC dependent cancers wherein the cancer is associated with at least oneof myc RNA expression or MYC protein expression. A patient can beidentified for such treatment by determining myc RNA expression or MYCprotein expression in the cancerous tissue or cells.

Diseases that can be treated with compounds of Formula (I) also includenon-cancerous proliferative disorders. Examples of proliferativedisorders that can be treated include, but are not limited to, benignsoft tissue tumors, bone tumors, brain and spinal tumors, eyelid andorbital tumors, granuloma, lipoma, meningioma, multiple endocrineneoplasia, nasal polyps, pituitary tumors, prolactinoma, pseudotumorcerebri, seborrheic keratoses, stomach polyps, thyroid nodules, cysticneoplasms of the pancreas, hemangiomas, vocal cord nodules, polyps, andcysts, Castleman disease, chronic pilonidal disease, dermatofibroma,pilar cyst, pyogenic granuloma, and juvenile polyposis syndrome.

The diseases and conditions that can be treated with the compounds ofFormula (I) also include chronic autoimmune and inflammatory conditions.Examples of autoimmune and inflammatory conditions that can be treatedinclude acute, hyperacute or chronic rejection of transplanted organs,acute gout, acute inflammatory responses (such as acute respiratorydistress syndrome and ischemia/reperfusion injury), Addison's disease,agammaglobulinemia, allergic rhinitis, allergy, alopecia, Alzheimer'sdisease, appendicitis, atherosclerosis, asthma, osteoarthritis, juvenilearthritis, psoriatic arthritis, rheumatoid arthriti, satopic dermatitis,autoimmune alopecia, autoimmune hemolytic and thrombocytopenic states,autoimmune hypopituitarism, autoimmune polyglandular disease, Behcet'sdisease, bullous skin diseases, cholecystitis, chronic idiopathicthrombocytopenic purpura, chronic obstructive pulmonary disease (COPD),cirrhosis, degenerative joint disease, depression, dermatitis,dermatomyositis, eczema, enteritis, encephalitis, gastritisglomerulonephritis, giant cell arteritis, Goodpasture's syndrome,Guillain-Barre syndrome, gingivitis, Graves' disease, Hashimoto'sthyroiditis, hepatitis, hypophysitis, inflammatory bowel disease(Crohn's disease and ulcerative colitis), inflammatory pelvic disease,irritable bowel syndrome, Kawasaki disease, LPS-induced endotoxic shock,meningitis, multiple sclerosis, myocarditis, myasthenia gravis, mycosisfungoides, myositis, nephritis, osteomyelitis, pancreatitis, Parkinson'sdisease, pericarditis, pernicious anemia, pneumonitis, primary biliarysclerosing cholangitis, polyarteritis nodosa, psoriasis, retinitis,scleritis, scleracierma, scleroderma, sinusitis, Sjogren's disease,sepsis, septic shock, sunburn, systemic lupus erythematosus, tissuegraft rejection, thyroiditis, type I diabetes, Takayasu's arteritis,urethritis, uveitis, vasculitis, vasculitis including giant cellarteritis, vasculitis with organ involvement such as glomerulonephritis,vitiligo, Waldenstrom macroglobulinemia and Wegener's granulomatosis.

The diseases and conditions that can be treated with the compounds ofFormula (I) also include diseases and conditions which involveinflammatory responses to infections with bacteria, viruses, fungi,parasites or their toxins, such as sepsis, sepsis syndrome, septicshock, endotoxaemia, systemic inflammatory response syndrome (SIRS),multi-organ dysfunction syndrome, toxic shock syndrome, acute lunginjury, ARDS (adult respiratory distress syndrome), acute renal failure,fulminant hepatitis, burns, acute pancreatitis, post-surgical syndromes,sarcoidosis, Herxheimer reactions, encephalitis, myelitis, meningitis,malaria, SIRS associated with viral infections such as influenza, herpeszoster, herpes simplex and coronavirus.

The diseases for which the compounds of Formula (I) are indicated alsoinclude diseases associated with a systemic inflammatory responsesyndrome, such as sepsis, burns, pancreatitis, major trauma, hemorrhageand ischemia. The compound of Formula (I) can be administered to reducethe incidence of: SIRS, the onset of shock, multi-organ dysfunctionsyndrome, which includes the onset of acute lung injury, ARDS, acuterenal, hepatic, cardiac and gastro-intestinal injury and mortality. Forexample, the compounds of the invention can be administered prior tosurgical or other procedures associated with a high risk of sepsis,hemorrhage, extensive tissue damage, SIRS or MODS.

Other diseases that can be treated with the compounds of Formula (I)include viral infections. Examples of viral infections that can betreated include Epstein-Barr virus, hepatitis B virus, hepatitis Cvirus, herpes virus, human immunodeficiency virus, human papillomavirus, adenovirus, poxvirus and other episome-based DNA viruses. Thecompounds can therefore be used to treat disease and conditions such asherpes simplex infections and reactivations, cold sores, herpes zosterinfections and reactivations, chickenpox, shingles, human papillomavirus, cervical neoplasia, adenovirus infections, including acuterespiratory disease, and poxvirus infections such as cowpox and smallpoxand African swine fever virus. In one particular embodiment thecompounds of Formula (I) are indicated for the treatment of humanpapilloma virus infections of skin or cervical epithelia.

The diseases and conditions that can be treated with the compounds ofFormula (I) also include conditions that are associated withischemia-reperfusion injury. Examples of such conditions include, butare not limited to conditions such as myocardial infarction,cerebrovascular ischemia (stroke), acute coronary syndromes, renalreperfusion injury, organ transplantation, coronary artery bypassgrafting, cardio-pulmonary bypass procedures and pulmonary, renal,hepatic, gastro-intestinal or peripheral limb embolism.

The compounds of Formula (I) are also useful in the treatment ofdisorders of lipid metabolism via the regulation of APO-A1 such ashypercholesterolemia, atherosclerosis and Alzheimer's disease.

The compounds of Formula (I) can also be used for the treatment offibrotic conditions such as idiopathic pulmonary fibrosis, renalfibrosis, post-operative stricture, keloid formation, scleroderma andcardiac fibrosis.

The compounds of Formula (I) can also be used to treat ophthalmologicalindications such as dry eye.

As used herein, the term “contacting” refers to the bringing together ofindicated moieties in an in vitro system or an in vivo system. Forexample, “contacting” a BET protein with a compound of the inventionincludes the administration of a compound of the present invention to anindividual or patient, such as a human, having a BET protein, as wellas, for example, introducing a compound of the invention into a samplecontaining a cellular or purified preparation containing the BETprotein.

As used herein, the term “individual” or “patient,” usedinterchangeably, refers to any animal, including mammals, preferablymice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep,horses, or primates, and most preferably humans.

As used herein, the phrase “therapeutically effective amount” refers tothe amount of active compound or pharmaceutical agent that elicits thebiological or medicinal response that is being sought in a tissue,system, animal, individual or human by a researcher, veterinarian,medical doctor or other clinician.

As used herein, the term “treating” or “treatment” refers to one or moreof (1) preventing the disease; for example, preventing a disease,condition or disorder in an individual who may be predisposed to thedisease, condition or disorder but does not yet experience or displaythe pathology or symptomatology of the disease; (2) inhibiting thedisease; for example, inhibiting a disease, condition or disorder in anindividual who is experiencing or displaying the pathology orsymptomatology of the disease, condition or disorder (i.e., arrestingfurther development of the pathology and/or symptomatology); and (3)ameliorating the disease; for example, ameliorating a disease, conditionor disorder in an individual who is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,reversing the pathology and/or symptomatology) such as decreasing theseverity of disease.

Combination Therapies

The compounds of Formula (I) can be used in combination treatments wherethe compound of the invention is administered in conjunction with othertreatment such as the administration of one or more additionaltherapeutic agents. The additional therapeutic agents are typicallythose which are normally used to treat the particular condition to betreated. The additional therapeutic agents can include, e.g.,chemotherapeutics, anti-inflammatory agents, steroids,immunosuppressants, as well as Bcr-Abl, Flt-3, RAF, FAK, and JAK kinaseinhibitors for treatment of BET protein-associated diseases, disordersor conditions. The one or more additional pharmaceutical agents can beadministered to a patient simultaneously or sequentially.

In some embodiments, the compounds of Formula (I) can be used incombination with a therapeutic agent that targets an epigeneticregulator. Examples of epigenetic regulators include the histone lysinemethyltransferases, histone arginine methyl transferases, histonedemethylases, histone deacetylases, histone acetylases, and DNAmethyltransferases. histone deacetylase inhibitors include, e.g.,vorinostat.

For treating cancer and other proliferative diseases, the compounds ofthe invention can be used in combination with chemotherapeutic agents,or other anti-proliferative agents. The compounds of the invention canalso be used in combination with medical therapy such as surgery orradiotherapy, e.g., gamma-radiation, neutron beam radiotherapy, electronbeam radiotherapy, proton therapy, brachytherapy, and systemicradioactive isotopes. Examples of suitable chemotherapeutic agentsinclude any of: abarelix, aldesleukin, alemtuzumab, alitretinoin,allopurinol, altretamine, anastrozole, arsenic trioxide, asparaginase,azacitidine, bevacizumab, bexarotene, bleomycin, bortezombi, bortezomib,busulfan intravenous, busulfan oral, calusterone, capecitabine,carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine,clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin,dalteparin sodium, dasatinib, daunorubicin, decitabine, denileukin,denileukin diftitox, dexrazoxane, docetaxel, doxorubicin, dromostanolonepropionate, eculizumab, epirubicin, erlotinib, estramustine, etoposidephosphate, etoposide, exemestane, filgrastim, floxuridine, fludarabine,fluorouracil, fulvestrant, gefitinib, gemcitabine, gemtuzumabozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuxetan,idarubicin, ifosfamide, imatinib mesylate, interferon alfa 2a,irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin,leuprolide acetate, levamisole, lomustine, meclorethamine, megestrolacetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mitomycinC, mitotane, mitoxantrone, nandrolone phenpropionate, nelarabine,nofetumomab, oxaliplatin, paclitaxel, pamidronate, panitumumab,pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin,pipobroman, plicamycin, procarbazine, quinacrine, rasburicase,rituximab, ruxolitinib, sorafenib, streptozocin, sunitinib, sunitinibmaleate, tamoxifen, temozolomide, teniposide, testolactone, thalidomide,thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab,tretinoin, uracil mustard, valrubicin, vinblastine, vincristine,vinorelbine, vorinostat, and zoledronate.

For treating cancer and other proliferative diseases, the compounds offormula (I) can be used in combination with ruxolitinib.

For treating autoimmune or inflammatory conditions, the compound ofFormula (I) can be administered in combination with a corticosteroidsuch as triamcinolone, dexamethasone, fluocinolone, cortisone,prednisolone, or flumetholone.

For treating autoimmune or inflammatory conditions, the compound ofFormula (I) can be administered in combination with an immunesuppressant such as fluocinolone acetonide (Retisert®), rimexolone(AL-2178, Vexol, Alcon), or cyclosporine (Restasis®).

For treating autoimmune or inflammatory conditions, the compound ofFormula (I) can be administered in combination with one or moreadditional agents selected from Dehydrex™ (Holles Labs), Civamide(Opko), sodium hyaluronate (Vismed, Lantibio/TRB Chemedia), cyclosporine(ST-603, Sirion Therapeutics), ARG101(T) (testosterone, Argentis),AGR1012(P) (Argentis), ecabet sodium (Senju-Ista), gefarnate (Santen),15-(s)-hydroxyeicosatetraenoic acid (15(S)-HETE), cevilemine,doxycycline (ALTY-0501, Alacrity), minocycline, iDestrin™ (NP50301,Nascent Pharmaceuticals), cyclosporine A (Nova22007, Novagali),oxytetracycline (Duramycin, MOLI1901, Lantibio), CF101(2S,3S,4R,5R)-3,4-dihydroxy-5-[6-[(3-iodophenyl)methylamino]purin-9-yl]-N-methyl-oxolane-2-carbamyl,Can-Fite Biopharma), voclosporin (LX212 or LX214, Lux Biosciences),ARG103 (Agentis), RX-10045 (synthetic resolvin analog, Resolvyx), DYN15(Dyanmis Therapeutics), rivoglitazone (DE011, Daiichi Sanko), TB4(RegeneRx), OPH-01 (Ophtalmis Monaco), PCS101 (Pericor Science), REV1-31(Evolutec), Lacritin (Senju), rebamipide (Otsuka-Novartis), OT-551(Othera), PAI-2 (University of Pennsylvania and Temple University),pilocarpine, tacrolimus, pimecrolimus (AMS981, Novartis), loteprednoletabonate, rituximab, diquafosol tetrasodium (INS365, Inspire), KLS-0611(Kissei Pharmaceuticals), dehydroepiandrosterone, anakinra, efalizumab,mycophenolate sodium, etanercept (Embrel®), hydroxychloroquine, NGX267(TorreyPines Therapeutics), or thalidomide.

In some embodiments, the compound of Formula (I) can be administered incombination with one or more agents selected from an antibiotic,antiviral, antifungal, anesthetic, anti-inflammatory agents includingsteroidal and non-steroidal anti-inflammatories, and anti-allergicagents. Examples of suitable medicaments include aminoglycosides such asamikacin, gentamycin, tobramycin, streptomycin, netilmycin, andkanamycin; fluoroquinolones such as ciprofloxacin, norfloxacin,ofloxacin, trovafloxacin, lomefloxacin, levofloxacin, and enoxacin;naphthyridine; sulfonamides; polymyxin; chloramphenicol; neomycin;paramomycin; colistimethate; bacitracin; vancomycin; tetracyclines;rifampin and its derivatives (“rifampins”); cycloserine; beta-lactams;cephalosporins; amphotericins; fluconazole; flucytosine; natamycin;miconazole; ketoconazole; corticosteroids; diclofenac; flurbiprofen;ketorolac; suprofen; cromolyn; lodoxamide; levocabastin; naphazoline;antazoline; pheniramine; or azalide antibiotic.

Other examples of agents, one or more of which a compound of Formula (I)may also be combined with include: a treatment for Alzheimer's Diseasesuch as donepezil and rivastigmine; a treatment for Parkinson's Diseasesuch as L-DOPA/carbidopa, entacapone, ropinirole, pramipexole,bromocriptine, pergolide, trihexyphenidyl, and amantadine; an agent fortreating multiple sclerosis (MS) such as beta interferon (e.g., Avonex®and Rebif®), glatiramer acetate, and mitoxantrone; a treatment forasthma such as albuterol and montelukast; an agent for treatingschizophrenia such as zyprexa, risperdal, seroquel, and haloperidol; ananti-inflammatory agent such as a corticosteroid, such as dexamethasoneor prednisone, a TNF blocker, IL-1 RA, azathioprine, cyclophosphamide,and sulfasalazine; an immunomodulatory agent, includingimmunosuppressive agents, such as cyclosporin, tacrolimus, rapamycin,mycophenolate mofetil, an interferon, a corticosteroid,cyclophosphamide, azathioprine, and sulfasalazine; a neurotrophic factorsuch as an acetylcholinesterase inhibitor, an MAO inhibitor, aninterferon, an anti-convulsant, an ion channel blocker, riluzole, or ananti-Parkinson's agent; an agent for treating cardiovascular diseasesuch as a beta-blocker, an ACE inhibitor, a diuretic, a nitrate, acalcium channel blocker, or a statin; an agent for treating liverdisease such as a corticosteroid, cholestyramine, an interferon, and ananti-viral agent; an agent for treating blood disorders such as acorticosteroid, an anti-leukemic agent, or a growth factor; or an agentfor treating immunodeficiency disorders such as gamma globulin.

In some embodiments, the compounds of the invention can be used incombination with one or more therapeutic agents selected from: Januskinase inhibitors (e.g., ruxolitinib, tofacitinib, baricitinib, CYT387,GLPG0634, lestaurtinib, pacritinib, TG101348), Pim kinase inhibitors,PI3 kinase inhibitors (including PI3K-delta selective and broad spectrumPI3K inhibitors), MEK inhibitors, cyclin dependent kinase inhibitors,b-RAF inhibitors, mTOR inhibitors, proteasome inhibitors (e.g.,bortezomib, carfilzomib), HDAC-inhibitors (e.g., panobinostat,vorinostat), DNA methyl transferase inhibitors, dexamethasone,melphalan, and immunomodulators such as lenolidomide and pomalidomide.In some embodiments, the Janus kinase inhibitor is selective for JAK1.In some embodiments, the Janus kinase inhibitor is selective for JAK1and JAK2.

IV. Formulation, Dosage Forms and Administration

When employed as pharmaceuticals, the compounds of Formula (I) can beadministered in the form of pharmaceutical compositions. Thesecompositions can be prepared in a manner well known in thepharmaceutical art, and can be administered by a variety of routes,depending upon whether local or systemic treatment is desired and uponthe area to be treated. Administration may be topical (includingtransdermal, epidermal, ophthalmic and to mucous membranes includingintranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalationor insufflation of powders or aerosols, including by nebulizer;intratracheal or intranasal), oral or parenteral. Parenteraladministration includes intravenous, intra-arterial, subcutaneous,intraperitoneal intramuscular or injection or infusion; or intracranial,e.g., intrathecal or intraventricular, administration. Parenteraladministration can be in the form of a single bolus dose, or may be, forexample, by a continuous perfusion pump. Pharmaceutical compositions andformulations for topical administration may include transdermal patches,ointments, lotions, creams, gels, drops, suppositories, sprays, liquidsand powders. Conventional pharmaceutical carriers, aqueous, powder oroily bases, thickeners and the like may be necessary or desirable.

This invention also includes pharmaceutical compositions which contain,as the active ingredient, the compound of the invention or apharmaceutically acceptable salt thereof, in combination with one ormore pharmaceutically acceptable carriers (excipients). In someembodiments, the composition is suitable for topical administration. Inmaking the compositions of the invention, the active ingredient istypically mixed with an excipient, diluted by an excipient or enclosedwithin such a carrier in the form of, for example, a capsule, sachet,paper, or other container. When the excipient serves as a diluent, itcan be a solid, semi-solid, or liquid material, which acts as a vehicle,carrier or medium for the active ingredient. Thus, the compositions canbe in the form of tablets, pills, powders, lozenges, sachets, cachets,elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solidor in a liquid medium), ointments containing, for example, up to 10% byweight of the active compound, soft and hard gelatin capsules,suppositories, sterile injectable solutions, and sterile packagedpowders.

In preparing a formulation, the active compound can be milled to providethe appropriate particle size prior to combining with the otheringredients. If the active compound is substantially insoluble, it canbe milled to a particle size of less than 200 mesh. If the activecompound is substantially water soluble, the particle size can beadjusted by milling to provide a substantially uniform distribution inthe formulation, e.g., about 40 mesh.

The compounds of the invention may be milled using known millingprocedures such as wet milling to obtain a particle size appropriate fortablet formation and for other formulation types. Finely divided(nanoparticulate) preparations of the compounds of the invention can beprepared by processes known in the art, e.g., see International App. No.WO 2002/000196.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate, and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

The compositions can be formulated in a unit dosage form, each dosagecontaining from about 5 to about 1, 000 mg (1 g), more usually about 100mg to about 500 mg, of the active ingredient. The term “unit dosageforms” refers to physically discrete units suitable as unitary dosagesfor human subjects and other mammals, each unit containing apredetermined quantity of active material calculated to produce thedesired therapeutic effect, in association with a suitablepharmaceutical excipient.

In some embodiments, the compositions of the invention contain fromabout 5 mg to about 50 mg of the active ingredient. One having ordinaryskill in the art will appreciate that this embodies compounds orcompositions containing about 5 mg to about 10 mg, about 10 mg to about15 mg, about 15 mg to about 20 mg, about 20 mg to about 25 mg, about 25mg to about 30 mg, about 30 mg to about 35 mg, about 35 mg to about 40mg, about 40 mg to about 45 mg, or about 45 mg to about 50 mg of theactive ingredient.

In some embodiments, the compositions of the invention contain fromabout 50 mg to about 500 mg of the active ingredient. One havingordinary skill in the art will appreciate that this embodies compoundsor compositions containing about 50 mg to about 100 mg, about 100 mg toabout 150 mg, about 150 mg to about 200 mg, about 200 mg to about 250mg, about 250 mg to about 300 mg, about 350 mg to about 400 mg, or about450 mg to about 500 mg of the active ingredient.

In some embodiments, the compositions of the invention contain fromabout 500 mg to about 1, 000 mg of the active ingredient. One havingordinary skill in the art will appreciate that this embodies compoundsor compositions containing about 500 mg to about 550 mg, about 550 mg toabout 600 mg, about 600 mg to about 650 mg, about 650 mg to about 700mg, about 700 mg to about 750 mg, about 750 mg to about 800 mg, about800 mg to about 850 mg, about 850 mg to about 900 mg, about 900 mg toabout 950 mg, or about 950 mg to about 1, 000 mg of the activeingredient.

The active compound may be effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It willbe understood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, the active ingredient istypically dispersed evenly throughout the composition so that thecomposition can be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulation isthen subdivided into unit dosage forms of the type described abovecontaining from, for example, about 0.1 to about 1000 mg of the activeingredient of the present invention.

The tablets or pills of the present invention can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permit theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol, and cellulose acetate.

The liquid forms in which the compounds and compositions of the presentinvention can be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions can be nebulized by use of inert gases. Nebulized solutionsmay be breathed directly from the nebulizing device or the nebulizingdevice can be attached to a face masks tent, or intermittent positivepressure breathing machine. Solution, suspension, or powder compositionscan be administered orally or nasally from devices which deliver theformulation in an appropriate manner.

Topical formulations can contain one or more conventional carriers. Insome embodiments, ointments can contain water and one or morehydrophobic carriers selected from, for example, liquid paraffin,polyoxyethylene alkyl ether, propylene glycol, white vaseline, and thelike. Carrier compositions of creams can be based on water incombination with glycerol and one or more other components, e.g.,glycerinemonostearate, PEG-glycerinemonostearate and cetylstearylalcohol. Gels can be formulated using isopropyl alcohol and water,suitably in combination with other components such as, for example,glycerol, hydroxyethyl cellulose, and the like. In some embodiments,topical formulations contain at least about 0.1, at least about 0.25, atleast about 0.5, at least about 1, at least about 2, or at least about 5wt % of the compound of the invention. The topical formulations can besuitably packaged in tubes of, for example, 100 g which are optionallyassociated with instructions for the treatment of the select indication,e.g., psoriasis or other skin condition.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration, and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated aswell as by the judgment of the attending clinician depending uponfactors such as the severity of the disease, the age, weight and generalcondition of the patient, and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers, or stabilizers willresult in the formation of pharmaceutical salts.

The therapeutic dosage of a compound of the present invention can varyaccording to, for example, the particular use for which the treatment ismade, the manner of administration of the compound, the health andcondition of the patient, and the judgment of the prescribing physician.The proportion or concentration of a compound of the invention in apharmaceutical composition can vary depending upon a number of factorsincluding dosage, chemical characteristics (e.g., hydrophobicity), andthe route of administration. For example, the compounds of the inventioncan be provided in an aqueous physiological buffer solution containingabout 0.1 to about 10% w/v of the compound for parenteraladministration. Some typical dose ranges are from about 1 μg/kg to about1 g/kg of body weight per day. In some embodiments, the dose range isfrom about 0.01 mg/kg to about 100 mg/kg of body weight per day. Thedosage is likely to depend on such variables as the type and extent ofprogression of the disease or disorder, the overall health status of theparticular patient, the relative biological efficacy of the compoundselected, formulation of the excipient, and its route of administration.Effective doses can be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems.

The compositions of the invention can further include one or moreadditional pharmaceutical agents such as a chemotherapeutic, steroid,anti-inflammatory compound, or immunosuppressant, examples of which arelisted hereinabove.

V. Labeled Compounds and Assay Methods

In another aspect, the present disclosure provides labeled compounds ofFormula (I) (radio-labeled, fluorescent-labeled, etc.) that can beuseful not only in imaging techniques but also in assays, both in vitroand in vivo, for localizing and quantitating BET proteins in tissuesamples, including human, and for identifying BET protein ligands byinhibition binding of a labeled compound. Accordingly, the disclosureprovides BET protein assays that contain such labeled compounds.

An “isotopically” or “radio-labeled” compound is a compound of theinvention where one or more atoms are replaced or substituted by an atomhaving an atomic mass or mass number different from the atomic mass ormass number typically found in nature (i.e., naturally occurring).Suitable radionuclides that may be incorporated in compounds of thepresent invention include but are not limited to ³H (also written as Tfor tritium), ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ¹⁸F, ³⁵S, ³⁶Cl,⁸²Br, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br, ¹²³I, ¹²⁴I, ¹²⁵I and ¹³¹I. The radionuclide thatis incorporated in the instant radio-labeled compounds will depend onthe specific application of that radio-labeled compound. For example,for in vitro BET protein labeling and competition assays, compounds thatincorporate ³H, ¹⁴C, ⁸²Br, ¹²⁵, ¹³¹I, ³⁵S or will generally be mostuseful. For radio-imaging applications ¹¹C, ¹⁸F, ¹²⁵I, ¹²³I, ¹²⁴I, ¹³¹I,⁷⁵Br, ⁷⁶Br or ⁷⁷Br will generally be most useful.

It is to be understood that a “radio-labeled” or “labeled compound” is acompound that has incorporated at least one radionuclide. In someembodiments the radionuclide is selected from the group consisting of³H, ¹⁴C, ¹²⁵I, ³⁵S and ⁸²Br. In some embodiments, the compoundincorporates 1, 2, or 3 deuterium atoms. Synthetic methods forincorporating radio-isotopes into organic compounds are known in theart.

The present invention can further include synthetic methods forincorporating radio-isotopes into compounds of the invention. Syntheticmethods for incorporating radio-isotopes into organic compounds are wellknown in the art, and an ordinary skill in the art will readilyrecognize the methods applicable for the compounds of invention.

A labeled compound of the invention can be used in a screening assay toidentify/evaluate compounds. For example, a newly synthesized oridentified compound (i.e., test compound) which is labeled can beevaluated for its ability to bind a BET protein by monitoring itsconcentration variation when contacting with the BET protein, throughtracking of the labeling. For example, a test compound (labeled) can beevaluated for its ability to reduce binding of another compound which isknown to bind to a BET protein (i.e., standard compound). Accordingly,the ability of a test compound to compete with the standard compound forbinding to the BET protein directly correlates to its binding affinity.Conversely, in some other screening assays, the standard compound islabeled and test compounds are unlabeled. Accordingly, the concentrationof the labeled standard compound is monitored in order to evaluate thecompetition between the standard compound and the test compound, and therelative binding affinity of the test compound is thus ascertained.

VI. Kits

The present invention also includes pharmaceutical kits useful, forexample, in the treatment or prevention of BET protein-associateddiseases or disorders, such as cancer, which include one or morecontainers containing a pharmaceutical composition comprising atherapeutically effective amount of a compound of Formula (I), or any ofthe embodiments thereof. Such kits can further include, if desired, oneor more of various conventional pharmaceutical kit components, such as,for example, containers with one or more pharmaceutically acceptablecarriers, additional containers, etc., as will be readily apparent tothose skilled in the art. Instructions, either as inserts or as labels,indicating quantities of the components to be administered, guidelinesfor administration, and/or guidelines for mixing the components, canalso be included in the kit.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of non-criticalparameters which can be changed or modified to yield essentially thesame results. The compounds of the Examples were found to be inhibitorsof one or more BET proteins as described below.

EXAMPLES Example 17-(3,5-Dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one

Step 1. 5-Nitro-3-phenyl-2H-1,4-benzoxazine

The 2-bromoacetophenone (3.9 g, 19 mmol) [Aldrich, cat. #115835] wasadded portion wise to a stirred suspension of 2-amino-3-nitrophenol (2.5g, 16 mmol) [Aldrich, cat. #297003] and K₂CO₃ (3.4 g, 24 mmol) in MeCN(100 mL) at room temperature. The reaction was monitored by LC/MS. Afterstirring for 3 h the reaction was complete and then EtOAc added andsolution filtered to remove the solids and the organic layer was washedwith water, 1 N HCl, brine, dried over MgSO₄, filtered and concentratedto give 5-nitro-3-phenyl-2H-1,4-benzoxazine as a dark oil (4.1 g, 100%).LCMS calc. for C₁₄H₁₁N₂O₃ (M+H)⁺: m/z=255.3; found: 255.1.

Step 2. 3-Phenyl-3,4-dihydro-2H-1,4-benzoxazin-5-amine

The 5-nitro-3-phenyl-2H-1,4-benzoxazine oil was taken up in MeOH (50 mL)in a Parr shaker bottle, deoxygenated with nitrogen, the catalyst 10% Pdon carbon (0.25 g) was added, the reaction vessel was charged to 55 psiwith hydrogen and shaken. After 2 h the reaction was complete by LC/MS.The reaction was filtered to remove the catalyst and concentrated underreduced pressure to give 3-phenyl-3,4-dihydro-2H-1,4-benzoxazin-5-amineas a dark oil. (3.5 g, 97%). LCMS calc. for C₁₄H₁₅N₂O (M+H)⁺: m/z=227.1;found: 227.1. ¹H NMR (500 MHz, DMSO-d₆) δ 7.44 (d, J=7.4 Hz, 2H), 7.37(dd, J=7.5 Hz, 2H), 7.31 (t, J=7.2 Hz, 1H), 6.35 (dd, J=7.9 Hz, 1H),6.21 (dd, J=7.8, 1.0 Hz, 1H), 6.07 (d, J=7.9 Hz, 1H), 5.00 (s, 1H), 4.62(s, 2H), 4.44 (dd, J=4.9, 2.6 Hz, 1H), 4.21-4.13 (m, 1H), 3.87 (dd,J=10.4, 7.7 Hz, 1H).

Step 3. 4-Phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one

The 3-phenyl-3,4-dihydro-2H-1,4-benzoxazin-5-amine (0.95 g, 4.2 mmol)was dissolved in THF (30 mL) and DIPEA (1.5 mL, 8.4 mmol) at roomtemperature (room temperature). The N,N-carbonyldiimidazole (0.82 g, 5.0mmol) was added portion wise over 10 min. The reaction was heated to 70°C. for 1 h and allowed to cool to room temperature and stirredovernight. To the reaction mixture was added EtOAc, and then the mixturewas washed with water, sodium bicarbonate water and brine, then driedover magnesium sulfate and concentrated to give crude product as a darkoil. The oil was triturated with ethyl ether to give a precipitate. Thesolids were triturated twice with ethyl ether and then the solids werecollected and air dried to give4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one as abrown solid (0.51 g, 48%). LCMS calc. for C₁₅H₁₃N₂O₂ (M+H)⁺: m/z=253.1;found: 253.1. ¹H NMR (300 MHz, DMSO-d₆) δ 10.88 (s, 1H), 7.39-7.22 (m,3H), 7.15-7.04 (m, 2H), 6.88 (t, J=8.0 Hz, 1H), 6.67 (d, J=7.8 Hz, 1H),6.57 (d, J=8.2 Hz, 1H), 5.45 (s, 1H), 4.54 (dd, J=11.6, 2.2 Hz, 1H),4.37 (dd, J=11.6, 3.0 Hz, 1H).

Step 4.7-Bromo-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one

A mixture of4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (400 mg,2 mmol) and N-bromosuccinimide (310 mg, 1.7 mmol) in AcOH (10 mL) wasstirred at room temperature for 2 h. The reaction mixture was allowed tocool and was concentrated to remove AcOH. The residue was taken up inEtOAc and was washed with water saturated NaHCO₃, brine, dried overmagnesium sulfate, filtered and concentrated to give crude product. Theproduct was purified by flash column chromatography on a Biotage systemeluting with a hexane:EtOAc gradient (0-40%) to give7-bromo-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-oneas an amber oil (0.30 g, 60%). LCMS calc. for C₁₅H₁₂BrN₂O₂(M+H)⁺:m/z=331.1, 333.1; found: 331.0, 333.0. ¹H NMR (300 MHz, CD₃OD) δ7.42-7.23 (m, 3H), 7.23-7.09 (m, 3H), 6.70 (d, J=8.4 Hz, 1H), 5.46 (dd,J=2.6 Hz, 1H), 4.66 (dd, J=11.6, 2.4 Hz, 1H), 4.47 (dd, J=11.6, 3.1 Hz,1H).

Step 5.7-(3,5-Dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one

7-Bromo-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one(200 mg, 0.6 mmol) and3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole(160 mg, 0.72 mmol) [Aldrich, cat. #643882] were dissolved in1,4-dioxane (20 mL) and potassium carbonate (200 mg, 1 mmol) in water (8mL). The reaction was deoxygenated with nitrogen and the catalyst[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexedwith DCM (1:1) (20 mg, 0.03 mmol) was added. The reaction mixture wasdeoxygenated with nitrogen and was heated at 100° C. After heating for 2h the reaction was complete by LCMS. The reaction mixture was allowed tocool to room temperature, EtOAc was added and the mixture was washedwith water, brine, then dried over magnesium sulfate and concentrated togive the crude product. The product was purified on preparative HPLC ona C-18 column eluting with a water:MeCN gradient buffered pH 2 with TFAto give7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-oneas white solid (0.10 g, 50%). LCMS calc. for C₂₀H₁₈N₃O₃ (M+H)⁺:m/z=348.1; found: 348.1. ¹H NMR (500 MHz, DMSO-d₆) δ 10.96 (s, 1H),7.38-7.24 (m, 3H), 7.16 (d, J=7.2 Hz, 2H), 6.84 (d, J=8.0 Hz, 1H), 6.76(d, J=8.0 Hz, 1H), 5.47 (s, 1H), 4.57 (dd, J=11.6, 2.2 Hz, 1H), 4.40(dd, J=11.6, 3.1 Hz, 1H), 2.25 (s, 3H), 2.08 (s, 3H).

Example 1A7-(3,5-Dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one(Enantiomer 1) Example 1B7-(3,5-Dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one(Enantiomer 2)

The enantiomers were separated from racemic7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-onefrom Example 1, Step 5 by chiral column HPLC using a Phenomenex LuxCellulose-4 column, 5 micron, 21.2×250 mm, eluting 30% ethanol inhexanes with a flow rate of 18 mL/min., loading approx. 36 mg perinjection with UV, 220 nm detection to give peak 1 at: 14.32 min. andpeak 2 at: 18.89 min.

Enantiomer 1: Peak 1: Example 1A (more active enantiomer), LCMS calc.for C₂₀H₁₈N₃O₃ (M+H)⁺: m/z=348.1; found: 348.1. ¹H NMR (500 MHz,DMSO-d₆) δ 10.96 (s, 1H), 7.38-7.24 (m, 3H), 7.16 (d, J=7.2 Hz, 2H),6.84 (d, J=8.0 Hz, 1H), 6.76 (d, J=8.0 Hz, 1H), 5.47 (s, 1H), 4.57 (dd,J=11.6, 2.2 Hz, 1H), 4.40 (dd, J=11.6, 3.1 Hz, 1H), 2.25 (s, 3H), 2.08(s, 3H).

Enantiomer 1: Peak 2: Example 1B (less active enantiomer), LCMS calc.for C₂₀H₁₈N₃O₃ (M+H)⁺: m/z=348.1; found: 348.1. ¹H NMR (500 MHz,DMSO-d₆) δ 10.96 (s, 1H), 7.38-7.24 (m, 3H), 7.16 (d, J=7.2 Hz, 2H),6.84 (d, J=8.0 Hz, 1H), 6.76 (d, J=8.0 Hz, 1H), 5.47 (s, 1H), 4.57 (dd,J=11.6, 2.2 Hz, 1H), 4.40 (dd, J=11.6, 3.1 Hz, 1H), 2.25 (s, 3H), 2.08(s, 3H).

Example 27-(3,5-Dimethylisoxazol-4-yl)-1-methyl-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one

Sodium hydride in mineral oil 60% (3.2 mg, 0.13 mmol) was added to asolution of7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one(0.040 g, 0.10 mmol) from Example 1, Step 5 in DMF (3 mL) cooled in anice bath. The reaction mixture was stirred for 15 min. and methyl iodide(8 μL, 0.1 mmol) was added. The reaction mixture was stirred for 30 min.and was complete by LCMS. The reaction mixture was partitioned betweenwater and EtOAc. The organic layer was concentrated and purified onpreparative HPLC on a C-18 column eluting with a water:MeCN gradientbuffered pH 2 with TFA to give the title compound as a solid productsolid (0.015 g, 37%). LCMS calc. for C₂₁H₂₀N₃O₃ (M+H)⁺: m/z=362.1;found: 362.1. ¹H NMR (300 MHz, DMSO-d₆) δ 7.39-7.24 (m, 5H), 7.19-7.12(m, 2H), 5.52 (s, 1H), 4.59 (dd, J=9.2 Hz, 1H), 4.41 (dd, J=8.4 Hz, 1H),3.38 (s, 3H), 2.26 (s, 3H), 2.09 (s, 3H).

Example 37-(3,5-Dimethylisoxazol-4-yl)-5-methyl-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one

The title compound was prepared by methods analogous to Example 1 butusing 2-bromo-1-phenylpropan-1-one [Alfa Aesar, cat. # A10661] inStep 1. The product was purified by preparative HPLC on a C-18 columneluting with a water:MeCN gradient buffered pH 2 with TFA to give thetitle compound as a white amorphous solid (0.015 g, 37%). LCMS calc. forC₂₁H₂₀N₃O₃ (M+H)⁺: m/z=362.1; found: 362.1. ¹H NMR (500 MHz, DMSO-d₆) δ10.89 (s, 1H), 7.36-7.26 (m, 3H), 7.06-7.01 (m, 2H), 6.87 (d, J=8.0 Hz,1H), 6.76 (d, J=8.0 Hz, 1H), 5.30 (d, J=2.8 Hz, 1H), 4.62-4.54 (m, 1H),2.30 (s, 3H), 2.14 (s, 3H), 1.12 (d, J=6.4 Hz, 3H).

Example 44-[7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]benzonitrile

The title compound was prepared by methods analogous to Example 1 butusing 4-(2-bromoacetyl)benzonitrile [Aldrich, cat. #539392] in Step 1.The product was purified by preparative HPLC on a C-18 column elutingwith water:MeCN gradient buffered pH 2 with TFA to give the titlecompound as a white amorphous solid (0.021 g, 52%). LCMS calc. forC₂₁H₁₇N₄O₃ (M+H)⁺: m/z=373.1; found: 373.2. ¹H NMR (500 MHz, DMSO-d₆) δ11.03 (s, 1H), 7.83 (d, J=8.3 Hz, 2H), 7.37 (d, J=8.3 Hz, 2H), 6.86 (d,J=8.0 Hz, 1H), 6.78 (d, J=8.0 Hz, 1H), 5.60 (s, 1H), 4.60 (dd, J=11.7,2.4 Hz, 1H), 4.43 (dd, J=11.7, 3.1 Hz, 1H), 2.25 (s, 3H), 2.08 (s, 3H).

Example 57-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-3-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one

The title compound was prepared by methods analogous to Example 1 butusing 2-bromo-1-(pyridin-3-yl)ethanone [Oakwood, cat. #005885] inStep 1. The product was purified by preparative HPLC on a C-18 columneluting with water:MeCN gradient buffered pH 2 with TFA to give the TFAsalt of the title compound as a white amorphous solid (0.010 g, 25%).LCMS calc. for C₁₉H₁₇N₄O₃ (M+H)⁺: m/z=349.1; found: 349.1. ¹H NMR (500MHz, DMSO-d₆+TFA) δ 11.09 (s, 1H), 8.94 (bs, 2H), 8.37 (d, J=8.1 Hz,1H), 8.04 (s, 1H), 6.89 (d, J=8.0 Hz, 1H), 6.81 (d, J=8.0 Hz, 1H), 5.76(s, 1H), 4.65 (dd, J=11.7, 3.5 Hz, 1H), 4.53 (dd, J=11.7, 3.1 Hz, 1H),2.28 (s, 3H), 2.11 (s, 3H).

Example 67-(3,5-Dimethylisoxazol-4-yl)-4-(3-methoxyphenyl)-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one

The title compound was prepared by methods analogous to Example 1 butusing 2-bromo-1-(3-methoxyphenyl)ethanone [Aldrich, cat. #115673] inStep 1 and usingdicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladiumas catalyst in Step 5. The product was purified by preparative HPLC on aC-18 column eluting with a water:MeCN gradient buffered pH 2 with TFA togive the title compound as a white amorphous solid (0.015 g, 37%). LCMScalc. for C₂₁H₂₀N₃O₄ (M+H)⁺: m/z=378.1; found: 378.1. ¹H NMR (300 MHz,DMSO-d₆) δ 10.97 (s, 1H), 7.21 (t, J=7.9 Hz, 1H), 6.88-6.79 (m, 2H),6.77-6.71 (m, 2H), 6.63 (d, J=7.8 Hz, 1H), 5.42 (s, 1H), 4.57 (dd,J=11.5 Hz, 1H), 4.36 (dd, J=11.6, 2.9 Hz, 1H), 3.67 (s, 3H), 2.23 (s,3H), 2.06 (s, 3H).

Example 77-(3,5-Dimethylisoxazol-4-yl)-4-(2-methoxyphenyl)-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one

The title compound was prepared by methods analogous to Example 1 butusing 2-bromo-1-(2-methoxyphenyl)ethanone [Aldrich, cat. #100854] inStep 1 and usingdicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladiumas catalyst in Step 5. The product was purified by preparative HPLC on aC-18 column eluting with water:MeCN gradient buffered pH 2 with TFA togive the title compound as a white amorphous solid (0.010 g, 25%). LCMScalc. for C₂₁H₂₀N₃O₄ (M+H)⁺: m/z=378.1; found: 378.1. ¹H NMR (300 MHz,DMSO-d₆) δ 11.03 (s, 1H), 7.37-7.21 (m, 1H), 7.09 (d, J=7.6 Hz, 1H),6.91-6.74 (m, 3H), 6.38 (d, J=7.5 Hz, 1H), 5.61 (s, 1H), 4.49 (dd,J=11.5 Hz, 1H), 4.37 (dd, J=11.3, 3.0 Hz, 1H), 3.88 (s, 3H), 2.22 (s,3H), 2.05 (s, 3H).

Example 87-(3,5-Dimethylisoxazol-4-yl)-4-(2,4-difluorophenyl)-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one

The title compound was prepared by methods analogous to Example 1 butusing 2-bromo-1-(2,4-difluorophenyl)ethanone [Aldrich, cat. #595152] inStep 1 and usingdicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladiumas catalyst in Step 5. The product was purified by preparative HPLC on aC-18 column eluting with water:MeCN gradient buffered pH 2 with TFA togive the title compound as a white amorphous solid (0.018 g, 45%). LCMScalc. for C₂₀H₁₆F₂N₃O₃(M+H)⁺: m/z=384.1; found: 384.1. ¹H NMR (300 MHz,DMSO-d₆) δ 11.05 (s, 1H), 7.44-7.27 (m, 1H), 7.09-6.97 (m, 1H),6.95-6.82 (m, 2H), 6.78 (d, J=8.0 Hz, 1H), 5.62 (s, 1H), 4.54-4.36 (m,2H), 2.26 (s, 3H), 2.09 (s, 3H).

Example 97-(3,5-Dimethylisoxazol-4-yl)-2-methyl-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine

The title compound was prepared by methods analogous to Example 1 butusing 1,1,1-trimethoxyethane [Aldrich, cat. #237876] in Step 3. Theproduct was purified by preparative HPLC on a C-18 column eluting withwater:MeCN gradient buffered pH 2 with TFA to give the TFA salt of thetitle compound as a white amorphous solid (0.003 g, 7%). LCMS calc. forC₂₁H₂₀N₃O₂ (M+H)⁺: m/z=346.1; found: 346.2. ¹H NMR (500 MHz, DMSO-d₆) δ7.44-7.36 (m, 4H), 7.26 (d, J=8.4 Hz, 1H), 7.19 (d, J=5.8 Hz, 2H), 6.03(s, 1H), 4.72 (dd, J=11.8, 3.9 Hz, 1H), 4.64 (dd, J=11.7, 3.3 Hz, 1H),2.37 (s, 3H), 2.30 (s, 3H), 2.13 (s, 3H).

Example 107-(3,5-Dimethylisoxazol-4-yl)-1-(2-morpholin-4-ylethyl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one

Step 1.7-Bromo-1-(2-morpholin-4-ylethyl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one

To a 0° C. mixture of7-bromo-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one(0.065 g, 0.20 mmol) from Example 1, step 4 and4-(2-chloroethyl)morpholine hydrochloride (0.12 g, 0.63 mmol) in DMF (1mL) was added NaH in mineral oil (0.048 g, 1.2 mmol). The reactionmixture was stirred over a weekend. EtOAc and water were added. Theorganic layer was washed with water and brine, dried over Na₂SO₄ andevaporated to dryness to give an orange oil. The crude was purified byLCMS (C18 column eluting with a gradient MeCN/H₂O containing 0.15% NH₄OHat 5 mL/min.) and gave a white solid (7.7 mg, 9% yield). ¹H NMR (400MHz, CD₃OD/CDCl₃): d 7.31 (3H, m); 7.18 (3H, m); 6.65 (1H, d); 5.19 (1H,m); 4.61 (1H, m); 4.43 (1H, m); 3.99 (2H, m); 3.6 (4H, m); 2.65 (2H, m);2.51 (4H, m). LCMS calc. for C₂₆H₂₉N₄O₄ (M+H)⁺: m/z=; found: 444.1,446.1.

Step 2.7-(3,5-Dimethylisoxazol-4-yl)-1-(2-morpholin-4-ylethyl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][14]benzoxazin-2(1H)-one

A deoxygenated solution of7-(3,5-dimethylisoxazol-4-yl)-1-(2-morpholin-4-ylethyl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one(7.0 mg, 0.015 mmol),3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole(4.6 mg, 0.021 mmol),dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (0.0017 g, 0.0022 mmol) and potassium phosphate (0.013 g, 0.061mmol) in 1,4-dioxane (0.2 mL) and water (0.08 mL) was refluxed for 2 h.The reaction mixture was cooled to room temperature and then additionalreagents(3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole(4.6 mg), potassium phosphate (12 mg) and catalyst (2.7 mg)) were added.The solution mixture was deoxygenated and then refluxed for 2.3 h. EtOAcand water were added. The organic layer was washed with brine and thenconcentrated to give a pale orange glass/oil (22 mg). The crude productwas purified by LCMS (C18 column eluting with a gradient MeCN/H₂Ocontaining 0.15% NH₄OH at 5 mL/min.) and gave the title compound as awhite solid (7.6 mg, 95% yield). ¹H NMR (500 MHz, DMSO-d₆): d 7.35 (3H,m); 7.18 (2H, m); 7.0 (1H, m); 6.95 (1H, m); 5.55 (1H, m); 4.61 (1H, m);4.42 (1H, m); 3.99 (2H, m); 3.5 (4H, m); 2.63 (2H, m); 2.42 (4H, m);2.23 (3H, s); 2.08 (3H, s). LCMS calc. for C₂₁H₂₃BrN₃O₃ (M+H)⁺:m/z=460.2; found: 460.2.

Example 117-(3,5-Dimethyl-1H-pyrazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one

The title compound was prepared by methods analogous to Example 1 butusing added3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole[Aldrich,cat. #636010] in Step 5. The product was purified by preparative HPLC ona C-18 column eluting with water: MeCN gradient buffered pH 2 with TFAto give the title compound as a white amorphous solid (0.018 g, 45%).LCMS calc. for C₂₀H₁₉N₄O₂ (M+H)⁺: m/z=347.1; found: 347.2.

Example 127-(3-Methyl-1H-pyrazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one

The title compound was prepared by methods analogous to Example 1 butusing added3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole[Aldrich, cat. #706078] in Step 5. The product was purified bypreparative HPLC on a C-18 column eluting with water: MeCN gradientbuffered pH 2 with TFA to give the title compound as a white amorphoussolid (0.018 g, 45%). LCMS calc. for C₁₉H₁₇N₄O₂ (M+H)⁺: m/z=333.1;found: 333.2.

Example 137-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one

The title compound was prepared by methods analogous to Example 1 butusing 2-bromo-1-(pyridin-2-yl)ethanone HBr [Maybridge CC04005DA] inStep 1. The product was purified by preparative HPLC on a C-18 columneluting with a water:MeCN gradient buffered pH 2 with TFA to give theTFA salt of the title compound as a white amorphous solid (0.015 g,30%). LCMS calc. for C₁₉H₁₇N₄O₃ (M+H)⁺: m/z=349.1; found: 349.1. ¹H NMR(300 MHz, DMSO-d₆) δ 11.01 (s, 1H), 8.52 (d, J=4.8 Hz, 1H), 7.79 (td,1H), 7.32 (dd, J=7.5, 4.9 Hz, 1H), 7.12 (d, J=7.8 Hz, 1H), 6.83 (d,J=8.0 Hz, 1H), 6.76 (d, J=8.0 Hz, 1H), 5.52 (s, 1H), 4.76 (dd, 1H), 4.44(dd, J=11.4, 3.1 Hz, 1H), 2.22 (s, 3H), 2.05 (s, 3H).

Example 147-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one(Enantiomer 1) Example 157-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one(Enantiomer 2)

The enantiomers were prepared from racemic7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-onefrom Example 13, by chiral column HPLC using a Phenomenex LuxCellulose-C4 column, 5 micron, 21.2×250 mm, eluting with 60% ethanol inhexanes with a flow rate of 18 mL/min., loading approx. 36 mg perinjection with UV (220 nm) detection to give peak 1 at: 7.51 min. andpeak 2 at: 12.92 min.

Enantiomer 2. Peak 1: Example 15. LCMS calc. for C₁₉H₁₇N₄O₃ (M+H)⁺:m/z=349.1; found: 349.1. ¹H NMR (300 MHz, DMSO-d₆) δ 11.01 (s, 1H), 8.52(d, J=4.8 Hz, 1H), 7.79 (td, 1H), 7.32 (dd, J=7.5, 4.9 Hz, 1H), 7.12 (d,J=7.8 Hz, 1H), 6.83 (d, J=8.0 Hz, 1H), 6.76 (d, J=8.0 Hz, 1H), 5.52 (s,1H), 4.76 (dd, 1H), 4.44 (dd, J=11.4, 3.1 Hz, 1H), 2.22 (s, 3H), 2.05(s, 3H). This enantiomer is believed to have the S configuration basedon X-ray crystallography data.

Enantiomer 1. Peak 2: Example 14. LCMS calc. for C₁₉H₁₇N₄O₃ (M+H)⁺:m/z=349.1; found: 349.1. ¹H NMR (300 MHz, DMSO-d₆) δ 11.01 (s, 1H), 8.52(d, J=4.8 Hz, 1H), 7.79 (td, 1H), 7.32 (dd, J=7.5, 4.9 Hz, 1H), 7.12 (d,J=7.8 Hz, 1H), 6.83 (d, J=8.0 Hz, 1H), 6.76 (d, J=8.0 Hz, 1H), 5.52 (s,1H), 4.76 (dd, 1H), 4.44 (dd, J=11.4, 3.1 Hz, 1H), 2.22 (s, 3H), 2.05(s, 3H).

Example 167-(3,5-Dimethylisoxazol-4-yl)-4-(1-oxidopyridin-2-yl)-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one

Methyltrioxorhenium(VII) (2 mg, 0.008 mmol) was added to a solution of7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one(20 mg, 0.06 mmol) from Example 15, in tetrahydrofuran (2 mL) at roomtemperature and then 3.0 M hydrogen peroxide in water (0.04 mL) wasadded. The reaction mixture was heated to 80° C. for 20 min. allowed tocool and was diluted with water and EtOAc. The combined organic layerswere washed with brine, dried over MgSO₄, filtered and concentrated togive the crude product. The product was purified by preparative HPLC ona C-18 column eluting with a water: MeCN gradient buffered pH 10 to givethe title compound as a white amorphous solid (0.007 g, 30%). LCMS calc.for C₁₉H₁₇N₄O₄ (M+H)⁺: m/z=365.1; found: 365.1. 1H NMR (400 MHz,DMSO-d6) δ 11.12 (s, 1H), 8.37 (d, J=5.8 Hz, 1H), 7.39 (td, J=7.2, 6.5,2.0 Hz, 1H), 7.25 (td, J=7.7, 0.9 Hz, 1H), 6.84 (d, J=8.1 Hz, 1H), 6.77(d, J=8.0 Hz, 1H), 6.63 (dd, J=7.9, 2.0 Hz, 1H), 5.84 (d, J=2.2 Hz, 1H),4.78 (dd, J=11.6, 1.3 Hz, 1H), 4.36 (dd, J=11.6, 3.4 Hz, 1H), 2.17 (s,3H), 2.00 (s, 3H).

Example 174-Cyclohexyl-7-(3,5-dimethylisoxazol-4-yl)-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one

Step 1. 2-Bromo-1-cyclohexylethanone

Cyclohexyl methyl ketone (0.30 mL, 2.4 mmol) [Alfa Aesar cat# L05501]was dissolved in methanol (3.0 mL, 74 mmol) cooled in an ice bath andbromine (0.38 g, 2.4 mmol) was added drop wise. The mixture was stirredfor 2 h and then water (3.0 mL) was added and the reaction mixture wasallowed to stir for 4 h. The reaction mixture was extracted withEtOAc:hexane (3:1). The combined organic layer was washed with watersaturated potassium carbonate, brine, dried over magnesium sulfate andconcentrated to give as 2-bromo-1-cyclohexylethanone as a clear oil(0.49 g, 100%). ¹H NMR (300 MHz, CDCl₃) δ 3.96 (s, 2H), 2.86-2.55 (m,1H), 2.24-1.08 (m, 10H).

Step 2

The title compound was prepared by methods analogous to Example 1 butusing 2-bromo-1-cyclohexylethanone from Step 1 above. The product waspurified by preparative HPLC on a C-18 column eluting with a water:MeCNgradient buffered pH 2 with TFA to give the title compound as a whiteamorphous solid (0.010 g, 30%). LCMS calc. for C₂₀H₂₄N₃O₃ (M+H)⁺:m/z=354.1; found: 354.2. ¹H NMR (400 MHz, DMSO-d₆) δ 10.86 (s, 1H), 6.78(d, J=8.0 Hz, 1H), 6.68 (d, J=8.0 Hz, 1H), 4.65 (d, J=11.1 Hz, 1H), 4.04(d, J=6.4 Hz, 1H), 3.97 (dd, J=11.8, 2.9 Hz, 1H), 2.28 (s, 3H), 2.12 (s,3H), 1.82-1.51 (m, 6H), 1.13 (d, J=18.1 Hz, 5H).

Example 18A7-(3,5-Dimethylisoxazol-4-yl)-4-(tetrahydrofuran-2-yl)-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one(Diastereoisomer 1) Example 18B7-(3,5-Dimethylisoxazol-4-yl)-4-(tetrahydrofuran-2-yl)-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one(Diastereoisomer 2)

The title compound was prepared by methods analogous to Example 1, butusing 2-bromo-1-(furan-2-yl)ethanone in Step 1 and the furan was reducedto the tetrahydrofuran in Step 2. The product was purified bypreparative HPLC on a C-18 column eluting with a water: MeCN gradientbuffered pH2 to give the title compound as two separateddiastereoisomers

Diastereoisomer 1. Peak 1. Example 18A. Solid residue. LCMS calc. forC₁₈H₂₀N₃O₄ (M+H)⁺: m/z=342.1; found: 342.1.

Diastereoisomer 2. Peak 2. Example 18B. Solid residue. LCMS calc. forC₁₈H₂₀N₃O₄ (M+H)⁺: m/z=342.1; found: 342.1.

Example 197-(3,5-Dimethylisoxazol-4-yl)-4-(5-fluoropyridin-2-yl)-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one

Step 1. 2-(1-Ethoxyvinyl)-5-fluoropyridine

A mixture of 2-bromo-5-fluoropyridine (200 mg, 1 mmol),tributyl(1-ethoxyvinyl)tin (500 mg, 1 mmol), copper(I) iodide (20 mg,0.1 mmol) and bis(triphenylphosphine)palladium(II) chloride (50 mg, 0.07mmol) in MeCN (5 mL) was heated to 80° C. for 30 h. The reaction mixturewas allowed to cool to room temperature and was diluted with EtOAc,washed with 5% NH₄OH, brine, dried over MgSO₄, filtered and concentratedto give a crude oil. The product was purified by flash columnchromatography on silica gel eluting with a hexane; EtOAc gradient(0-30%) to give 2-(1-ethoxyvinyl)-5-fluoropyridine as a clear oil (0.2g, 90%). LCMS calc. for C₉H₁₁FNO (M+H)+: m/z=168.1; found: 168.2.

Step 2. 2-Bromo-1-(5-fluoropyridin-2-yl)ethanone

N-Bromosuccinimide (200 mg, 1 mmol) was added to a mixture of2-(1-ethoxyvinyl)-5-fluoropyridine (200 mg, 1 mmol) in THF (6 mL) andwater (2 mL). The reaction mixture was stirred at room temperature for15 min., diluted with EtOAc and washed with brine. The combined organiclayer was dried with MgSO₄, filtered and concentrated to give2-bromo-1-(5-fluoropyridin-2-yl)ethanone as a clear oil, which was usedin the next step.

Step 3.7-(3,5-Dimethylisoxazol-4-yl)-4-(5-fluoropyridin-2-yl)-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one

The title compound was prepared by methods analogous to Example 1, butusing 2-bromo-1-(5-fluoropyridin-2-yl)ethanone from above, in Step 1.The product was purified by preparative HPLC on a C-18 column elutingwith a water:MeCN gradient buffered pH2 to give the title compound as asolid residue. LCMS calc. for C₁₉H₁₆FN₄O₃(M+H)+: m/z=367.1; found:367.1.

Example 20 Ethyl7-(3,5-dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-5-carboxylate

Step 1. Ethyl 2-bromo-3-oxo-3-pyridin-2-ylpropanoate hydrobromide

Bromine (0.83 g, 5.2 mmol) in chloroform (2 mL) was added slowly to asolution of ethyl 3-oxo-3-pyridin-2-ylpropanoate (1.0 g, 5.2 mmol) andchloroform (25.0 mL) at room temperature. The reaction mixture wasstirred for 1 h and was concentrated under reduced pressure to give 1ethyl 2-bromo-3-oxo-3-pyridin-2-ylpropanoate hydrobromide salt as anamber oil (1.8 g, 100%). LCMS calc. for C₁₀H₁₁BrNO₃ (M+H)+: m/z=272.0,274.0; found: 272.0, 274.0.

Step 2. Ethyl7-(3,5-dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-5-carboxylate

The title compound was prepared by methods analogous to Example 1, butusing 2-bromo-3-oxo-3-pyridin-2-ylpropanoate from above, in Step 1. Theproduct was purified by preparative HPLC on a C-18 column eluting with awater:MeCN gradient buffered pH 10 to give a mixture of the twodiastereoisomers of the title compound as a solid residue. LCMS calc.for C₂₂H₂₁N₄O₅ (M+H)+: m/z=421.1; found: 421.1.

Example 217-(3,5-Dimethylisoxazol-4-yl)-4-(1,3-thiazol-2-yl)-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one

Step 1. 2-Bromo-1-(1,3-thiazol-2-yl)ethanone

Bromine (70 μL, 1 mmol) was added to a mixture of1-(1,3-thiazol-2-yl)ethanone (200 mg, 2 mmol) in AcOH (5 mL). Thereaction mixture was stirred at 100° C. for 30 min. and was concentratedunder reduced pressure to give 2-bromo-1-(1,3-thiazol-2-yl)ethanone asan oil (100%) used as crude.

Step 2.7-(3,5-dimethylisoxazol-4-yl)-4-(1,3-thiazol-2-yl)-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one

The title compound was prepared by a method analogous to Example 1, butusing 2-bromo-1-(1,3-thiazol-2-yl)ethanone from above, in Step 1. Theproduct was purified by preparative HPLC on a C-18 column eluting with awater:MeCN gradient buffered pH 2 to give the title compound as a solidresidue. LCMS calc. for C₁₇H₁₅N₄O₃S (M+H)+: m/z=355.1; found: 355.1. ¹HNMR (500 MHz, DMSO-d6) δ 11.05 (s, 1H), 7.78 (d, J=3.2 Hz, 1H), 7.69 (d,J=3.2 Hz, 1H), 6.85 (d, J=8.0 Hz, 1H), 6.77 (d, J=8.0 Hz, 1H), 5.90 (s,1H), 4.83 (d, J=10.4 Hz, 1H), 4.44 (dd, J=11.6, 2.9 Hz, 1H), 2.24 (s,3H), 2.07 (s, 3H).

Example 222-{2-[7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]phenoxy}-N-ethylacetamide

Step 1. Methyl (2-acetylphenoxy)acetate

1-(2-Hydroxyphenyl)ethanone (1.0 g, 7.3 mmol) and methyl bromoacetate(0.70 mL, 7.3 mmol) were combined in acetone (20.0 mL) with potassiumcarbonate (2.0 g, 15 mmol) and was stirred at room temperature. Thereaction mixture was stirred for 18 h, diluted with EtOAc and filteredto remove the solids. The organic layer was concentrated to give thesub-title compound as a clear oil (1.5 g, 100%). LCMS calc. forC₁₁H₁₃O₄(M+H)+: m/z=209.1; found: 209.1.

Step 2. Methyl [2-(bromoacetyl)phenoxy]acetate

Bromine (1.2 g, 7.2 mmol) in chloroform (5 mL) was added drop wise to asolution of methyl (2-acetylphenoxy)acetate (1.5 g, 7.2 mmol) inchloroform (45 mL) at room temperature. The reaction mixture was stirredfor 1 h at room temperature, diluted with EtOAc and washed with sodiumbicarbonate water, brine, dried over magnesium sulfate and concentratedto give the sub-title compound as an oil which solidified (2.1 g, 100%).LCMS calc. for C₁₁H₁₂BrO₄ (M+H)+: m/z=287.0, 289.0; found: 287.0, 289.0.

Step 3.{2-[7-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]phenoxy}aceticacid

The intermediate compound was prepared by methods analogous to Example1, but using methyl [2-(bromoacetyl)phenoxy]acetate from above, in Step1 and the ester was found to saponify in Step 5 to give the sub-titlecompound as a solid residue. LCMS calc. for C₂₂H₂₀N₃O₆ (M+H)+:m/z=422.1; found: 422.1.

Step 4.2-{2-[7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]phenoxy}-N-ethylacetamide

A mixture of{2-[7-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]phenoxy}aceticacid (0.03 g, 0.07 mmol) in DMF (2.0 mL) with DIPEA (0.025 mL, 0.14mmol) and HATU (0.027 g, 0.071 mmol) was stirred at room temperature for10 min. and ethylamine (0.0064 g, 0.14 mmol) was added. The reactionmixture was stirred for 1 h and the product was purified without workupby preparative HPLC on a C-18 column eluting with a water:MeCN gradientbuffered pH 2 buffered with TFA to give the title compound as anoff-white amorphous solid. LCMS calc. for C₂₄H₂₅N₄O₅ (M+H)+: m/z=449.1;found: 449.2.

Example 23 Ethyl7-(3,5-dimethylisoxazol-4-yl)-2-oxo-4-phenyl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-5-carboxylate

Step 1. Ethyl 2-bromo-3-oxo-3-phenylpropanoate

Ethyl benzoylacetate (0.27 mL, 1.6 mmol) [Fluka cat#12990] was dissolvedin dimethyl sulfoxide (5.0 mL) at room temperature and theN-bromosuccinimide (0.30 g, 1.7 mmol) was added portion wise. Thereaction mixture was stirred for 3 h and EtOAc was added and washed withwater, water saturated sodium bicarbonate, brine, dried over magnesiumsulfate and concentrated to give Ethyl 2-bromo-3-oxo-3-phenylpropanoate(0.40 g, 95%) as an oil %). LCMS calc. for C₁₁H₁₂BrO₃ (M+H)⁺: m/z=271.0,273.0; found: 271.0, 273.0.

Step 2. Ethyl7-(3,5-dimethylisoxazol-4-yl)-2-oxo-4-phenyl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-5-carboxylate

The title compound was prepared by a method analogous to Example 1, butusing ethyl 2-bromo-3-oxo-3-phenylpropanoate Step 1 above. The productwas purified by preparative HPLC on a C-18 column eluting with awater:MeCN gradient buffered pH 2 with TFA to give a mixture ofdiastereoisomers of the title compound as a white amorphous solid (0.012g, 25%). LCMS calc. for C₂₃H₂₂N₃O₅ (M+H)⁺: m/z=320.1; found: 320.2. ¹HNMR (300 MHz, DMSO-d₆) δ 11.01 (d, J=5.1 Hz, 1H), 7.38-7.19 (m, 3H),7.14-6.94 (m, 2H), 6.94-6.65 (m, 2H), 5.70 (s, 0.4H), 5.54 (t, J=2.4 Hz,1H), 5.36 (d, J=3.3 Hz, 0.6H), 3.99 (dq, J=14.2, 7.1 Hz, 2H), 2.29 (s,1.8H), 2.19 (s, 1.2H), 2.14 (s, 1.8H), 2.02 (s, 1.2H), 0.99 (dt, J=9.8,7.1 Hz, 3H).

Example 24A7-(3,5-Dimethylisoxazol-4-yl)-N-ethyl-2-oxo-4-phenyl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-5-carboxamide(Diastereoisomer 1) Example 24B7-(3,5-Dimethylisoxazol-4-yl)-N-ethyl-2-oxo-4-phenyl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-5-carboxamide(Diastereoisomer 2)

Step 1.7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-4-phenyl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-5-carboxylicacid

Ethyl7-(3,5-dimethylisoxazol-4-yl)-2-oxo-4-phenyl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-5-carboxylate(0.150 g, 0.358 mmol) from Example 23 was dissolved in MeOH (3.0 mL) andlithium hydroxide, monohydrate (0.030 g, 0.72 mmol) dissolved in water(1.0 mL) was added. The reaction mixture was stirred at room temperaturefor 2 h, diluted with EtOAc and washed with saturated water ammoniumchloride, brine, dried over magnesium sulfate and concentrated to give amixture of the diastereoisomers of the title compound as a solid residue(0.145 g, 100%). LCMS calc. for C₂₁H₁₈N₃O₅ (M+H)+: m/z=392.1; found:392.1.

Step 2.7-(3,5-Dimethylisoxazol-4-yl)-N-ethyl-2-oxo-4-phenyl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-5-carboxamide

7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-4-phenyl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-5-carboxylicacid (0.04 g, 0.1 mmol) was dissolved in DMF (2.0 mL) with DIPEA (0.036mL, 0.20 mmol) at room temperature. HATU (0.054 g, 0.14 mmol) was addedand then the 2.0 M ethylamine in THF (0.20 mL, 0.41 mmol) was added. Thereaction mixture was stirred at room temperature for an hour and wasdiluted with EtOAc. The organic layer was washed with 1 N HCl, brine,dried over magnesium sulfate and concentrated to give a solid. Theproduct was purified by preparative HPLC on a C-18 column eluting with awater:MeCN gradient buffered pH 2 to give the title compound as twoseparated diastereoisomers.

Diastereoisomer 1. Peak 1. Example 24A. Solid residue (0.010 g, 25%).LCMS calc. for C₂₃H₂₃N₄O₄ (M+H)⁺: m/z=419.1; found: 419.1.

Diastereoisomer 2. Peak 2. Example 24B. Solid residue (0.008 g, 20%).LCMS calc. for C₂₃H₂₃N₄O₄ (M+H)⁺: m/z=419.1; found: 419.1.

Example 257-(3,5-Dimethylisoxazol-4-yl)-N-isopropyl-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-amine

Step 1.2-Chloro-7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine

To7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one(40.0 mg, 0.115 mmol) in a vial, phosphoryl chloride (1.5 mL, 16 mmol)was added and the mixture was heated at 95° C. overnight. The mixturewas evaporated and extracted with EtOAc. The extracts were washed withsaturated sodium bicarbonate, brine and dried over sodium sulfate.Filtration and evaporation gave the desired compound (42 mg, 100%). LCMScalc. for C₂₀H₁₇ClN₃O₂(M+H)⁺: m/z=366.1; found: 366.1.

Step 2.7-(3,5-Dimethylisoxazol-4-yl)-N-isopropyl-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-amine

To2-chloro-7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine(9.1 mg, 0.025 mmol) in N-methylpyrrolidinone (0.40 mL), triethylamine(10 μL, 0.075 mmol) and 2-propanamine (21.2 μL, 0.25 mmol) were addedand the mixture was heated at 120° C. overnight. The mixture was dilutedwith MeOH and purified by preparative LCMS (pH 10) to give the desiredcompound (2.8 mg, 29%). ¹H NMR (500 MHz, DMSO-d₆): δ 7.29 (3H, m); 6.92(3H, m); 6.78 (1H, m); 6.55 (1H, m); 5.80 (1H, s); 4.68 (1H, m); 4.45(1H, m); 4.00 (1H, m); 2.20 (3H, s); 2.02 (3H, s); 1.20 (3H, m); 1.09(3H, m). LCMS calc. for C₂₃H₂₅N₄O₂ (M+H)⁺: m/z=389.2; found: 389.2.

Example 267-(3,5-Dimethylisoxazol-4-yl)-N-methyl-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-amine

The title compound was prepared by a method analogous to Example 25, butusing methylamine in Step 2. The product was purified by preparativeHPLC on a C-18 column eluting with a water:MeCN gradient buffered pH 10with ammonium hydroxide to give the title compound (2.1 mg, 13%). ¹H NMR(500 MHz, DMSO-d₆): d 7.29 (3H, m); 6.93 (3H, m); 6.83 (1H, m); 6.79(1H, m); 5.70 (1H, s); 4.61 (1H, m); 4.43 (1H, m); 2.87 (3H, m); 2.11(3H, s); 2.03 (3H, s); 1.49 (1H, m). LCMS calc. for C₂₁H₂₁N₄O₂ (M+H)⁺:m/z=361.2; found: 361.2.

Example 277-(3,5-Dimethylisoxazol-4-yl)-N-ethyl-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-amine

The title compound was prepared by methods analogous to Example 25, butusing ethyl amine in Step 2. The product was purified by preparativeHPLC on a C-18 column eluting with a water:MeCN gradient buffered pH 10with ammonium hydroxide to give the title compound (6.0 mg, 42%). ¹H NMR(500 MHz, DMSO-d₆): δ 7.29 (3H, m); 6.93 (3H, m); 6.87 (1H, m); 6.78(1H, m); 5.78 (1H, s); 4.63 (1H, m); 4.43 (1H, m); 3.32 (2H, m); 2.20(3H, s); 2.02 (3H, s); 1.12 (3H, m). LCMS calc. for C₂₂H₂₃N₄O₂ (M+H)⁺:m/z=375.2; found: 375.2.

Example 287-(3,5-Dimethylisoxazol-4-yl)-N,N-dimethyl-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-amine

The title compound was prepared by methods analogous to Example 25, butusing dimethylamine in Step 2. The product was purified by preparativeHPLC on a C-18 column eluting with a water:MeCN gradient buffered pH 10with ammonium hydroxide to give the title compound (6.7 mg, 72%). ¹H NMR(500 MHz, DMSO-d₆): δ 7.29 (3H, m); 7.00 (1H, m); 6.85 (3H, m); 6.11(1H, s); 4.52 (2H, m); 2.99 (6H, s); 2.20 (3H, s); 2.02 (3H, s). LCMScalc. for C₂₂H₂₃N₄O₂ (M+H)⁺: m/z=375.2; found: 375.2.

Example 292-{[7-(3,5-Dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]amino}ethanol

The title compound was prepared by a method analogous to Example 25, butusing ethanolamine [Aldrich #411000] in Step 2. The product was purifiedby preparative HPLC on a C-18 column eluting with a water:MeCN gradientbuffered pH 10 with ammonium hydroxide to give the title compound (5.5mg, 40%). LCMS calc. for C₂₂H₂₃N₄O₃ (M+H)⁺: m/z=391.2; found: 391.2.

Example 302-{[7-(3,5-Dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]amino}propan-1-ol(Diastereoisomer 1) Example 312-{[7-(3,5-Dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]amino}propan-1-ol(Diastereoisomer 2)

The title compound was prepared by a method analogous to Example 25, butusing DL-alaninol [Aldrich #192171] in Step 2. The product was purifiedby preparative HPLC on a C-18 column eluting with a water:MeCN gradientbuffered pH 10 with ammonium hydroxide to give the two racemicdiastereoisomers of the title compound.

Diastereoisomer 1. Peak I. Example 30 (3.9 mg, 27%). ¹H NMR (500 MHz,DMSO-d₆): δ 7.30 (4H, m); 6.92 (3H, m); 6.79 (1H, m); 6.53 (1H, m); 5.82(1H, s); 4.76 (1H, m); 4.68 (1H, m); 4.43 (1H, m); 3.92 (1H, m); 3.45(1H, m); 3.20 (1H, m); 2.20 (3H, s); 2.03 (3H, s); 1.19 (3H, m). LCMScalc. for C₂₃H₂₅N₄O₃ (M+H)⁺: m/z=405.2; found: 405.2.

Diastereoisomer 2. Peak 2. Example 31. LCMS calc. for C₂₃H₂₅N₄O₃ (M+H)⁺:m/z=405.2; found: 405.2.

Example 321-{[7-(3,5-Dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]amino}propan-2-ol

The title compound was prepared by a method analogous to Example 25, butusing 1-amino-2-propanol [Aldrich #110248] in Step 2. The product waspurified by preparative HPLC on a C-18 column eluting with a water:MeCNgradient buffered pH 10 with ammonium hydroxide to give the titlecompound (5.3 mg, 37%) as a mixture of diastereoisomers. LCMS calc. forC₂₃H₂₅N₄O₃ (M+H)⁺: m/z=405.2; found: 405.2.

Example 332-{[7-(3,5-Dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]amino}-2-methylpropan-1-ol

The title compound was prepared by a method analogous to Example 25, butusing 2-amino-2-methyl-1-propanol [Aldrich #A65182] in Step 2. Theproduct was purified by preparative HPLC on a C-18 column eluting with awater:MeCN gradient buffered pH 10 with ammonium hydroxide to give thetitle compound (1.5 mg, 10%). LCMS calc. for C₂₄H₂₇N₄O₃ (M+H)⁺:m/z=419.2; found: 419.2.

Example 342-[[7-(3,5-Dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl](methyl)amino]ethanol

The title compound was prepared by a method analogous to Example 25, butusing 2-(methylamino)ethanol [Aldrich #471445] in Step 2. The productwas purified by preparative HPLC on a C-18 column eluting with awater:MeCN gradient buffered pH 10 with ammonium hydroxide to give thetitle compound (2.6 mg, 18%). LCMS calc. for C₂₃H₂₅N₄O₃ (M+H)⁺:m/z=405.2; found: 405.2.

Example 357-(1-Methyl-1H-pyrazol-5-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one

7-Bromo-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one(100 mg, 0.3 mmol) was dissolved in 1,4-dioxane (2.4 mL). A solution of1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (94mg, 0.45 mmol) and potassium phosphate (100 mg, 0.6 mmol) in water (0.60mL) was added. Reaction was deoxygenated with nitrogen.Dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (7 mg, 0.009 mmol) was added and deoxygenated with nitrogen. Thereaction mixture was stirred at 100° C. for 4 h. Water and EtOAc wereadded and the layers were separated. The organic layer was concentratedunder reduced pressure. Purification on silica using EtOAc/hexanes gavethe title compound (61 mg). LCMS calc. for C₁₉H₁₇N₄O₂ (M+H)⁺: m/z=333.1;found: 333.2. ¹H NMR (300 MHz, DMSO-d₆): d 7.40 (s, 1H); 7.31 (m, 3H);7.13 (m, 2H); 6.92 (m, 1H); 6.79 (m, 1H); 6.22 (s, 1H); 5.49 (s, 1H);4.59 (m, 1H); 4.41 (m, 1H); 3.60 (s, 3H).

Example 369-Bromo-7-(1-methyl-1H-pyrazol-5-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one

To a solution of7-(1-methyl-1H-pyrazol-5-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one(32 mg, 0.096 mmol) in THF (0.7 mL) was added N-bromosuccinimide (19 mg,0.10 mmol). The solution was stirred at room temperature for 1 h andthen concentrated under reduced pressure. Purification on silica gelusing EtOAc/hexane gave the title compound, 24 mg. LCMS calc. forC₁₉H₁₆BrN₄O₂(M+H)⁺: m/z=411.0, 413.0; found: 411.1, 413.1. ¹H NMR (300MHz, DMSO-d₆): d 7.40 (s, 1H); 7.31 (m, 3H); 7.13 (m, 2H); 7.08 (s, 1H);6.30 (s, 1H); 5.50 (s, 1H); 4.59 (m, 1H); 4.41 (m, 1H); 3.60 (s, 3H).

Example 379-Methyl-7-(1-methyl-1H-pyrazol-5-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one

A reaction mixture of9-bromo-7-(1-methyl-1H-pyrazol-5-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one(17 mg, 0.04 mmol), a solution of 2.0 M methylzinc chloride in THF (0.10mL) and tetrakis(triphenylphosphine)palladium(0) (2 mg, 0.002 mmol) inTHF (0.5 mL) under nitrogen was heated in a microwave at 130° C. for 5min. The title compound was purified by preparative LCMS using a pH10buffer. LCMS calc. for C₂₀H₁₉N₄O₂ (M+H)⁺: m/z=347.1; found: 347.2.

Example 387-(4-Chloro-1-methyl-1H-pyrazol-5-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one

Step 1.4-Chloro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

A mixture of1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(1.3 g, 6.3 mmol), N-chlorosuccinimide (0.93 g, 7.0 mmol) and THF (6.6mL) was stirred at 70° C. for 3 h. The mixture was extracted with EtOAc,dried and concentrated under reduced pressure. The sub-title compoundwas purified by chromatography on silica gel using 40% EtOAc in hexanesgave the desired compound, 1.456 g, 95%.

Step 2.7-(4-Chloro-1-methyl-1H-pyrazol-5-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one

The title compound was prepared by a method analogous to Example 35, butusing4-chloro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.The product was purified by preparative HPLC on a C-18 column elutingwith water:MeCN gradient buffered at pH2 to give the title compound.LCMS calc. for C₁₉H₁₆ClN₄O₂(M+H)⁺: m/z=367.1; found: 367.1.

Example 397-(3,5-Dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine

A reaction mixture of2-chloro-7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine(15 mg, 0.041 mmol), 0.5 M bromo(propyl)zinc in THF (0.5 mL) andtetrakis(triphenylphosphine)palladium(0) (2 mg, 0.002 mmol) in THF (0.4mL) under nitrogen was heated in a microwave at 150° C. for 5 min.Purification of the product by preparative LCMS using pH 10 buffer gavethe title compound. LCMS calc. for C₂₀H₁₇N₃O₂ (M+H)⁺: m/z=332.1; found:332.2.

Example 407-(3,5-Dimethylisoxazol-4-yl)-4-phenyl-2-piperazin-1-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine

4-[7-(3,5-Dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperazine-1-carboxylate(Example 60) was stirred in 4 N HCl for 15 min. at room temperature andevaporated. Purification by preparative LCMS at pH 10 gave the desiredcompound which was isolated as the dihydrochloride salt. LCMS calc. forC₂₄H₂₆N₅O₂ (M+H)⁺: m/z=416.2; found: 416.2.

Example 417-(3,5-Dimethylisoxazol-4-yl)-2,4-diphenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine

A mixture of2-chloro-7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine(14 mg, 0.039 mmol), phenylboronic acid (5.6 mg, 0.046 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith DCM (1:1) (2 mg, 0.002 mmol) and potassium carbonate (16 mg, 0.12mmol) in 1,4-dioxane (0.2 mL), and water (0.1 mL). The resulting mixturewas heated at 80° C. for 3 h. The reaction mixture was diluted with MeOHand purified on Preparative LCMS using pH 10 buffer to give the desiredcompound.

LCMS calc. for C₂₆H₂₂N₃O₂ (M+H)⁺: m/z=408.2; found: 408.2.

Example 427-(3,5-Dimethylisoxazol-4-yl)-2-oxo-4-phenyl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-9-carbonitrile

9-Bromo-7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one(6.9 mg, 0.016 mmol), zinc cyanide (19 mg, 0.16 mmol) andtetrakis(triphenylphosphine)palladium(0) (2.8 mg, 0.0024 mmol) weredissolved in DMF (1.6 mL) and the solution was deoxygenated. The stirredreaction mixture was heated at 150° C. in a microwave for 5 min. Themixture was diluted with MeOH and purified by preparative LCMS using pH10 buffer to give the title compound. LCMS calc. for C₂₁H₁₇N₄O₃ (M+H)⁺:m/z=373.1; found: 373.2.

Example 437-(3,5-Dimethylisoxazol-4-yl)-4,9-diphenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one

A mixture of9-bromo-7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one(9.0 mg, 0.021 mmol), phenylboronic acid (3.1 mg, 0.025 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith DCM (1:1) (0.9 mg, 0.001 mmol) and potassium carbonate (8.8 mg,0.063 mmol) in 1,4-dioxane (0.1 mL), and water (0.07 mL) was heated at80° C. for 3 h. The reaction mixture was diluted with MeOH and purifiedon by preparative LCMS using a pH 10 buffer to give the title compound.LCMS calc. for C₂₆H₂₂N₃O₃ (M+H)⁺: m/z=424.2; found: 424.0.

Example 447-(1,4-Dimethyl-1H-pyrazol-5-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one

Step 1.1,4-Dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

1,4-Dimethyl-1H-pyrazole (50 mg, 0.5 mmol) was stirred in THF (2 mL) andcooled to 0° C. A solution of 1.6 M n-butyllithium in hexanes (390 mL)was added dropwise by syringe and the mixture was allowed to warm toroom temperature for 2 h. The mixture was cooled to −78° C. and2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (110 mL, 0.52 mmol)was added dropwise by syringe. The mixture was stirred at −78° C. for 15min. and at 0° C. for 3 h. The mixture was diluted with EtOAc and washedwith brine, dried over sodium sulfate, filtered and concentrated underreduced pressure. Purification by chromatography on silica gel usingEtOAc in hexanes gave the sub-title compound. LCMS calc. forC₁₁H₂₀BN₂O₂(M+H)⁺: m/z=223.2; found: 223.0.

Step 2.7-(1,4-dimethyl-1H-pyrazol-5-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one

7-Bromo-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one(28 mg, 0.084 mmol) was dissolved in 1,4-dioxane (0.67 mL).1,4-Dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(28 mg, 0.13 mmol) and potassium phosphate (40 mg, 0.2 mmol) in water(0.17 mL) was added. The reaction mixture was deoxygenated withnitrogen.Dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (2 mg, 0.002 mmol) was added and the mixture was againdeoxygenated with nitrogen. The reaction mixture was then stirred at 90°C. under nitrogen for 2 h. Product was purified using preparative LCMS(pH 10) to give the title compound. LCMS calc. for C₁₉H₁₇N₅O₂(M+H)⁺:m/z=348.1; found: 348.0.

Example 459-Bromo-7-(3,5-Dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one

The title compound was prepared by methods analogous to Example 36, butusing7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one.LCMS calc. for C₂₀H₁₇BrN₃O₃(M+H)⁺: m/z=426.0; found: 426.0.

Example 467-(3,5-Dimethylisoxazol-4-yl)-9-methyl-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one

The title compound was prepared by methods analogous to Example 37, butusing9-bromo-7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one.LCMS calc. for C₂₁H₂₀N₃O₃ (M+H)⁺: m/z=362.1; found: 362.2.

Examples 47A-52

The experimental procedures used to prepare the compounds of Examples47A to 52 are summarized in Table 1 below. Examples 47A and 47B andExamples 48A and 48B are pairs of diastereoisomers which werechromatographically separated by methods analogous to the separationsdescribed above.

TABLE 1

Example No. Name R¹ R⁷ Cy³ Proc.¹ 47A 7-(3,5-Dimethylisoxazol-4-yl)-N,N-dimethyl-2-oxo-4-phenyl- 1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-5- carboxamide (Diastereoisomer 1)

H Ph 23 47B 7-(3,5-Dimethylisoxazol-4-yl)- N,N-dimethyl-2-oxo-4-phenyl-1,2,4,5-tetrahydroimidazo[1,5,4- de][1,4]benzoxazine-5- carboxamide(Diastereoisomer 2)

H Ph 23 48A 7-(3,5-Dimethylisoxazol-4-yl)-N-(2-hydroxyethyl)-2-oxo-4-phenyl- 1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-5- carboxamide (Diastereoisomer 1)

H Ph 23 48B 7-(3,5-Dimethylisoxazol-4-yl)-N-(2-hydroxyethyl)-2-oxo-4-phenyl- 1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-5- carboxamide (Diastereoisomer 2)

H Ph 23 49 7-(3,5-Dimethylisoxazol-4-yl)-4- (4-fluorophenyl)-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazin-2(1H)-one H H

 1 50 2-{2-[7-(3,5-Dimethylisoxazol-4- yl)-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4- de][1,4]benzoxazin-4- yl]phenoxy}-N-(2-hydroxyethyl)acetamide H H

23 51 2-{2-[7-(3,5-Dimethylisoxazol-4- yl)-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4- de][1,4]benzoxazin-4- yl]phenoxy}-N,N-dimethylacetamide H H

23 52 7-(3,5-Dimethylisoxazol-4-yl)-4- phenyl-9-pyridin-3-yl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazin-2(1H)-one H

Ph 43 ¹Synthesized according to an experimental procedure analogous tothat used for the synthesis of the Example compound indicated.

Examples 53-60

The experimental procedures used to prepare the compounds of Examples 53to 61 are summarized in Table 2 below.

TABLE 2

Ex- am- Pro- ple ce- No. Name R⁵ Cy³ dure¹ 53 7-(3,5-Dimethylisoxazol-4-yl)-2-morpholin-4-yl-4- phenyl-4,5- dihydroimidazo[1,5,4-de][1,4]benzoxazine

Ph 25 54 7-(3,5-Dimethylisoxazol- 4-yl)-4-phenyl-2- pyrrolidin-1-yl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazine

Ph 25 55 1-[7-(3,5- Dimethylisoxazol-4-yl)- 4-phenyl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazin-2- yl]pyrrolidin-3-ol

Ph 25 56 7-(3,5-Dimethylisoxazol- 4-yl)-4-phenyl-2- piperidin-1-yl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazine

Ph 25 57 1-[7-(3,5- Dimethylisoxazol-4-yl)- 4-phenyl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazin-2- yl]piperidin-4-ol

Ph 25 58 1-[7-(3,5- Dimethylisoxazol-4-yl)- 4-phenyl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazin-2- yl]piperidin-3-ol

Ph 25 59 1-[7-(3,5-(3,5- Dimethylisoxazol-4-yl)- 4-phenyl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazin-2- yl]azetidin-3-ol

Ph 25 60 4-[7-(3,5- Dimethylisoxazol-4-yl)- 4-phenyl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazin-2- yl]piperazine-1- carboxylate

Ph 25 ¹Synthesized according to the experimental procedure of compoundlisted;

Example 61A7-(3,5-Dimethylisoxazol-4-yl)-5,5-dimethyl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one(Diastereoisomer 1) Example 61B7-(3,5-Dimethylisoxazol-4-yl)-5,5-dimethyl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one(Diastereoisomer 2)

Step 1. 2-Bromo-2-methyl-1-(pyridin-2-yl)propan-1-one

Bromine (2.1 g, 13.4 mmol) dissolved in acetic acid (1 mL) was addedslowly to a mixture of 2-methyl-(1-pyridin-2-yl)propan-1-one (2.0 g, 13mmol) in acetic acid (20 mL) at room temperature. The reaction washeated to 105° C. for 3 h, allowed to cool to room temperature, andconcentrated in vacuo to give a dark semisolid. The crude product waspartitioned between ethyl acetate and saturated aqueous sodiumbicarbonate. The combined organic layer was washed with brine, driedover magnesium sulfate, and concentrated to give2-bromo-2-methyl-1-(pyridin-2-yl)propan-1-one as a very dark oil (3.0 g,98%). LCMS calculated for C₉H₁₁BrNO (M+H)⁺: m/z=227.9, 229.9; found:228.1, 230.1.

Step 2.7-(3,5-Dimethylisoxazol-4-yl)-5,5-dimethyl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one

The title compound was prepared by methods analogous to Example 13, butusing 2-bromo-2-methyl-1-(pyridin-2-yl)propan-1-one in Step 1. Theproduct was purified by prep HPLC on a C-18 column eluting awater:acetonitrile gradient buffered at pH 10 to give the title compoundas a mixture of diastereomers. The isomers were separated by prep chiralcolumn chromatography using the following conditions: Column: phenomenexLux Cellulose C-2 5 μm, 21, 2×250 mm, Mobile phase: 45% EtOH/Hexanes,gradient condition: isocratic at 18 mL/min, Loading: 13.0 mg in 900 μL,run time: 18 min, peak time: 9.0, and 12.0 min.

Diastereoisomer 1, Peak 1 as a solid residue. LCMS calculated forC₂₁H₂₁N₄O₃ (M+H)⁺: m/z=377.1; found: 377.1. 1H NMR (400 MHz, DMSO-d6) δ10.87 (s, 1H), 8.41 (dt, J 4.0, 0.9 Hz, 1H), 7.74 (td, J 7.7, 1.8 Hz,1H), 7.27 (ddd, J 7.6, 4.8, 1.1 Hz, 1H), 7.11 (d, J 7.9 Hz, 1H), 6.84(d, J 8.0 Hz, 1H), 6.71 (d, J 8.0 Hz, 1H), 5.24 (s, 1H), 2.27 (s, 3H),2.11 (s, 3H), 1.36 (s, 3H), 1.11 (s, 3H).

Diastereoisomer, Peak 2 as a solid residue. LCMS calculated forC₂₁H₂₁N₄O₃ (M+H)⁺: m/z=377.1; found: 377.1. 1H NMR (400 MHz, DMSO-d6) δ10.87 (s, 1H), 8.41 (dt, J 4.0, 0.9 Hz, 1H), 7.74 (td, J 7.7, 1.8 Hz,1H), 7.27 (ddd, J 7.6, 4.8, 1.1 Hz, 1H), 7.11 (d, J 7.9 Hz, 1H), 6.84(d, J 8.0 Hz, 1H), 6.71 (d, J 8.0 Hz, 1H), 5.24 (s, 1H), 2.27 (s, 3H),2.11 (s, 3H), 1.36 (s, 3H), 1.11 (s, 3H).

Example 62A7-(3,5-Dimethylisoxazol-4-yl)-5-(hydroxymethyl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one(Diastereoisomer 1) Example 62B7-(3,5-Dimethylisoxazol-4-yl)-5-(hydroxymethyl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one(Diastereoisomer 2) Example 62C7-(3,5-Dimethylisoxazol-4-yl)-5-(hydroxymethyl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one(Diastereoisomer 3) Example 62D7-(3,5-Dimethylisoxazol-4-yl)-5-(hydroxymethyl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one(Diastereoisomer 4)

Lithium tetrahydroborate (1.6 mg, 0.071 mmol) was added to ethyl7-(3,5-dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-5-carboxylate(20 mg, 0.05 mmol), from Example 20, in tetrahydrofuran (3 mL). Thereaction was stirred at 70° C. for 3 h, then partitioned between waterand ethyl acetate. The organic layer was concentrated and the crudeproduct was purified by FCC on silica gel eluting a hexane:ethyl acetategradient to obtain the product as a mixture of diastereomers. Theisomers were separated by prep chiral column chromatography using thefollowing conditions: Column: phenomenex Lux Cellulose C-2 5 μm, 21,2×250 mm, Mobile phase: 45% EtOH/Hexanes, Gradient condition: isocraticat 18 mL/min, Loading: 13.5 mg in 900 μL, run time: 18 min, peak time:9.0, 12.1, 24.2 and 15.0 min.

Diastereoisomer 1, Peak 1 as a solid residue. LCMS calculated forC₂₀H₁₉N₄O₄ (M+H)⁺: m/z=379.1; found: 379.1.

Diastereoisomer 2, Peak 2 as a solid residue. LCMS calculated forC₂₀H₁₉N₄O₄ (M+H)⁺: m/z=379.1; found: 379.1. ¹H NMR (400 MHz, DMSO-d6) δ10.93 (s, 1H), 8.47 (d, J 4.1 Hz, 1H), 7.79-7.65 (m, 1H), 7.26 (dd, J7.0, 5.2 Hz, 1H), 7.01 (d, J 7.9 Hz, 1H), 6.76 (d, J 8.0 Hz, 1H), 6.67(d, J 8.0 Hz, 1H), 5.37 (d, J 3.2 Hz, 1H), 5.22 (t, J 5.4 Hz, 1H),4.71-4.57 (m, 1H), 3.45 (q, J=5.5 Hz, 2H), 2.17 (s, 3H), 2.01 (s, 3H).

Diastereoisomer 3, Peak 3 as a solid residue. LCMS calculated forC₂₀H₁₉N₄O₄ (M+H)⁺: m/z=379.1; found: 379.1.

Diastereoisomer 4, Peak 4 as a solid residue. LCMS calculated forC₂₀H₁₉N₄O₄ (M+H)⁺: m/z=379.1; found: 379.1.

Example 63A7-(3,5-Dimethylisoxazol-4-yl)-4-piperidin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one2,2,2-trifluoroacetate (Diastereoisomer 1) Example 63B7-(3,5-Dimethylisoxazol-4-yl)-4-piperidin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one2,2,2-trifluoroacetate (Diastereoisomer 2)

Step 1.4-Piperidin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one

The tricycle intermediate,4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one(0.25 g, 0.98 mmol) from Example 13, was partially dissolved in methanol(50.0 mL) and 12.0 M hydrogen chloride in water (1.0 mL, 12 mmol) in aParr bottle. The reaction was degassed with nitrogen, followed byaddition of palladium (10% on carbon), and the reaction was charged to55 PSI hydrogen and shaken for 6 days. The reaction was filtered toremove the catalyst and concentrated in vacuo to give4-piperidin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-oneas a dark oil (0.21 g, 82%). LCMS calculated for C₁₄H₁₈N₃O₂ (M+H)⁺:m/z=260.1; found: 260.1.

Step 2.7-Bromo-4-piperidin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one

The4-piperidin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one(0.20 g, 0.77 mmol) of Step 1 was dissolved in acetic acid (10.0 mL, 176mmol) at room temperature and N-bromosuccinimide (0.14 g, 0.77 mmol) wasslowly added. The reaction was stirred for 2 h and was concentrated invacuo to give a residue. The residue was dissolved in ethyl acetate,washed with aqueous potassium carbonate, washed with brine, dried overmagnesium sulfate, and concentrated to give7-bromo-4-piperidin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-oneas a dark oil (0.22 g, 85%). LCMS calculated for C₁₄H₁₇BrN₃O₂ (M+H)⁺:m/z=338.0, 340.0; found: 338.0, 340.0.

Step 3.7-(3,5-Dimethylisoxazol-4-yl)-4-piperidin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one2,2,2-trifluoroacetate

The7-bromo-4-piperidin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one(0.025 g, 0.074 mmol) of Step 2 was combined with(3,5-dimethylisoxazol-4-yl)boronic acid (0.016 g, 0.11 mmol) in1,4-dioxane (3.0 mL) with potassium carbonate (0.02 g, 0.15 mmol) inwater (0.38 mL) and was degassed with nitrogen. The catalyst[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1) (0.006 g, 0.007 mmol) was added and the reactionwas heated in a sealed tube to 100° C. After stirring for 2 h thereaction was allowed to cool to room temperature and was partitionedbetween ethyl acetate and water. The organic layer was washed withbrine, dried over magnesium sulfate, and concentrated to give the crudeproduct as a dark oil. The product was purified by prep HPLC on a C-18column eluting a water:acetonitrile gradient buffered at pH 2 with TFAto give7-(3,5-dimethylisoxazol-4-yl)-4-piperidin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-oneas two fractions.

Diastereoisomer 1, Peak 1 as a solid residue (0.008 g, 30%). LCMScalculated for C₁₉H₂₃N₄O₃ (M+H)⁺: m/z=355.1; found: 355.1. ¹H NMR (400MHz, DMSO-d₆) δ 11.13 (d, J 12.8 Hz, 1H), 8.78 (d, J 8.6 Hz, 1H), 6.86(d, J 8.0 Hz, 1H), 6.78 (d, J 8.0 Hz, 1H), 4.79 (d, J 12.3 Hz, 1H), 4.42(dd, J 8.7, 2.1 Hz, 1H), 4.02 (dd, J 12.3, 2.8 Hz, 1H), 3.37 (s, 2H),3.26 (d, J 10.5 Hz, 2H), 2.84 (s, 1H), 2.28 (s, 3H), 2.12 (s, 3H), 2.01(d, J 13.3 Hz, 1H), 1.75 (d, J=13.2 Hz, 1H), 1.64-1.52 (m, 1H), 1.47 (s,1H).

Diastereoisomer 2, Peak 2 as a solid residue (0.007 g, 27%). LCMScalculated for C₁₉H₂₃N₄O₃ (M+H)⁺: m/z=355.1; found: 355.1.

Example 69A7-(3,5-Dimethylisoxazol-4-yl)-4-methyl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one(Diastereoisomer 1) Example 69B7-(3,5-Dimethylisoxazol-4-yl)-4-methyl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one(Diastereoisomer 2)

Step 1. 2-(2-Amino-3-nitrophenoxy)-1-pyridin-3-ylethanone

2-Bromo-1-(pyridin-3-yl)ethanone hydrobromide (600 mg, 2 mmol) (HBrsalt) was added to a mixture of 2-amino-3-nitrophenol (300 mg, 2 mmol)and potassium carbonate (400 mg, 3 mmol) in acetone (30 mL, 400 mmol) atroom temperature. The reaction was stirred at room temperature for 18 h,was diluted with water, and was then extracted with ethyl acetate. Thecombined organic layers were washed with brine, dried over magnesiumsulfate, filtered, and concentrated to give crude2-(2-amino-3-nitrophenoxy)-1-pyridin-3-ylethanone (0.35 g, 60%). LCMScalculated for C₁₃H₁₂N₃O₄ (M+H)⁺: m/z=274.1; found: 274.1.

Step 2. 2-Nitro-6-[(2-pyridin-2-ylprop-2-en-1-yl)oxy]aniline

Potassium tert-butoxide (1.10 g, 9.9 mmol) was added to a suspension ofmethyl triphenylphosphonium bromide (3.0 g, 8 mmol) in tetrahydrofuran(30 mL) under nitrogen. The reaction was stirred at room temperature for1 h, followed by addition of2-(2-amino-3-nitrophenoxy)-1-pyridin-2-ylethanone (2 g, 8 mmol). Themixture was stirred for 3 h, and was then partitioned between water andethyl ether. The organic layer was washed with brine, dried overmagnesium sulfate, filtered, and concentrated to give the crude product.The product was purified by FCC on silica gel eluting with ahexane:ethyl acetate gradient to give2-nitro-6-[(2-pyridin-2-ylprop-2-en-1-yl)oxy]aniline as light brownsolid (0.5 g, 20%). LCMS calculated for C₁₄H₁₄N₃O₃ (M+H)⁺: m/z=272.1;found: 272.1.

Step 3. 2-{1-[(2-Azido-3-nitrophenoxy)methyl]vinyl}pyridine

Sodium nitrite (100 mg, 2 mmol) in water (4 mL, 60 mmol) was added to asolution of 2-nitro-6-[(2-pyridin-2-ylprop-2-en-1-yl)oxy]aniline (350mg, 1.3 mmol) in 4.0 M hydrogen chloride in water (4 mL, 10 mmol) at 0°C. The reaction was stirred for 5 min and was then neutralized to pH 6-7with solid sodium bicarbonate. Sodium azide (80 mg, 1 mmol) in water (2mL) was added drop-wise to the mixture, followed by stirring for 30 min,over which time the reaction mixture became a thick slurry. Theresulting mixture was filtered and dried to give2-{1-[(2-azido-3-nitrophenoxy)methyl]vinyl}pyridine as a dark yellowsolid (0.25 g. 83%). LCMS calculated for C₁₄H₁₂N₅O₃ (M+H)⁺: m/z=298.1;found: 298.1.

Step 4.7-Nitro-1a-pyridin-2-yl-1a,2-dihydro-1H-azireno[2,1-c][1,4]benzoxazine

A mixture of 2-{1-[(2-azido-3-nitrophenoxy)methyl]vinyl}pyridine (250mg, 0.84 mmol) in benzene (15 mL) was refluxed at 80° C. for 15 h. Thereaction was concentrated to give the crude product. The product waspurified by FCC on silica gel eluting with a hexane:ethyl acetategradient to give7-nitro-1a-pyridin-2-yl-1a,2-dihydro-1H-azireno[2,1-c][1,4]benzoxazineas a solid (0.225 g, 90%). LCMS calculated for C₁₄H₁₂N₃O₃ (M+H)⁺:m/z=270.1; found: 270.1.

Step 5. 3-Methyl-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazin-5-amine

A mixture of7-nitro-1a-pyridin-2-yl-1a,2-dihydro-1H-azireno[2,1-c][1,4]benzoxazine(100 mg, 0.4 mmol) in methanol (6 mL) and tetrahydrofuran (2 mL) wasdegassed with nitrogen in a Parr bottle followed by addition ofpalladium (10% on carbon) (30 mg, 0.28 mmol). The reaction was chargedwith hydrogen to 40 psi and shaken for 6 hrs. The reaction was filteredand concentrated to give crude3-methyl-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazin-5-amine (0.030 g.30%). LCMS calculated for C₁₄H₁₆N₃O (M+H)⁺: m/z=242.1; found: 242.1.

Step 6.4-Methyl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one

Triphosgene (40 mg, 0.1 mmol) was added to the solution of3-methyl-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazin-5-amine (90 mg,0.4 mmol) in tetrahydrofuran (10 mL) and N,N-diisopropylethylamine (100μL) at room temperature. The reaction was stirred for 1 h and was thenpartitioned between ethyl acetate and water. The organic layer waswashed with brine, dried over magnesium sulfate, filtered, andconcentrated to give crude4-methyl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-oneas a semisolid (0.10 g. 90%). LCMS calculated for C₁₅H₁₄N₃O₂ (M+H)⁺:m/z=268.1; found: 268.0.

Step 7.7-Bromo-4-methyl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one

N-Bromosuccinimide (60 mg, 0.3 mmol) was added to a solution of4-methyl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one(90 mg, 0.3 mmol), acetic acid (6 mL) and acetonitrile (6 mL) at 0° C.The reaction mixture was stirred for 1 h at 0° C., quenched with water,and was concentrated to give the crude product. The crude product wasdissolved in ethyl acetate and washed with saturated aqueous sodiumbicarbonate. The combined organic layer was washed with brine, driedover magnesium sulfate, filtered, and concentrated to give a dark oil.The product was purified by FCC on silica gel eluting a hexane:ethylacetate gradient containing 20% ethanol to give7-bromo-4-methyl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-oneas an off white solid (0.090 g. 80%). LCMS calculated forC₁₅H₁₃BrN₃O₂(M+H)⁺: m/z=346.1, 348.1; found: 345.9, 347.9.

Step 8.7-(3,5-Dimethylisoxazol-4-yl)-4-methyl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][,4]benzoxazin-2(1H)-one

7-Bromo-4-methyl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one(80 mg, 0.2 mmol) was combined in 1,4-dioxane (10 mL) with potassium(3,5-dimethylisoxazol-4-yl)(trifluoro)borate (0.070 g, 0.35 mmol) andpotassium carbonate (60 mg, 0.5 mmol) in water (5 mL), and was degassedwith nitrogen. The catalyst[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1) (30 mg, 0.04 mmol) was added and the reaction wasstirred at 80° C. for 4 h, at which time reaction mixture was allowed tocool to room temperature and was partitioned between water and ethylacetate. The combined organic layers were washed with brine, dried overmagnesium sulfate and concentrated to give the crude product. Theproduct was purified by FCC on silica gel eluting a hexane:ethyl acetategradient containing 20% ethanol to give7-(3,5-dimethylisoxazol-4-yl)-4-methyl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-oneas a clear oil. The enantiomers were separated on chiral column usingthe following conditions: Phenomenex Lux Cellulose C-4, 5 μm, 21×2×250mm; mobile phase: 45% ethanol in Hexanes gradient: 18 mL/min isocratic;Run time: 11 min; Loading: 4 mg in 900 μL; Peak time: 7.1 & 8.8 min.

Diastereoisomer 1, Peak 1, as a white amorphous solid (0.010 g. 10%).LCMS calculated for C₂₀H₁₉N₄O₃ (M+H)⁺: m/z=363.1; found: 363.1. ¹H NMR(500 MHz, DMSO-d₆) δ 11.02 (s, 1H), 8.55 (d, J=4.5 Hz, 1H), 7.83-7.69(m, 1H), 7.29 (dd, J=7.3, 4.9 Hz, 1H), 7.06 (d, J=8.0 Hz, 1H), 6.80 (d,J=8.0 Hz, 1H), 6.73 (d, J=8.0 Hz, 1H), 4.79 (d, J=11.1 Hz, 1H), 4.19 (d,J=11.1 Hz, 1H), 2.17 (s, 3H), 1.99 (s, 3H), 1.95 (s, 3H).

Diastereoisomer 2, Peak 2, as a white amorphous solid (0.010 g. 10%).LCMS calculated for C₂₀H₁₉N₄O₃ (M+H)⁺: m/z=363.1; found: 363.1.

Example 707-(3,5-Dimethylisoxazol-4-yl)-4-ethyl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one2,2,2-trifluoroacetate

Step 1. 5-Nitro-3-pyridin-2-yl-2H-1,4-benzoxazine

The mixture of 5-nitro-3-pyridin-2-yl-2H-1,4-benzoxazine and5-nitro-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazin-3-ol (intermediate,Example 13) (200 mg, 0.7 mmol) was dissolved in acetonitrile (0.2 mL)and acetic acid (0.8 mL) at room temperature and stirred for 10 min. Thereaction was diluted with acetonitrile (15 mL) and concentrated at roomtemperature to remove residual acetic acid to give5-nitro-3-pyridin-2-yl-2H-1,4-benzoxazine as a light green solid (0.20g. 100%). LCMS calculated for C₁₃H₁₀N₃O₃ (M+H)⁺: m/z=256.1; found:255.9.

Step 2. 3-Ethyl-5-nitro-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazine

0.5 M Ethyl lithium in benzene-cyclohexane (1.8 mL, 0.88 mmol) was addeddrop-wise to a solution of 5-nitro-3-pyridin-2-yl-2H-1,4-benzoxazine(0.025 g, 0.88 mmol) in tetrahydrofuran (4 mL), cooled to −78° C. Thereaction was stirred for 1 h at −78° C. and was then quenched withmethanol. The reaction mixture was partitioned between ethyl acetate andwater, and the organic layer was washed with brine, dried over magnesiumsulfate, filtered, and concentrated to give crude product. The productwas purified by FCC on silica gel eluting a hexane:ethyl acetategradient to give3-ethyl-5-nitro-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazine as a solid(0.021 g. 84%). LCMS calculated for C₁₅H₁₆N₃O₃ (M+H)⁺: m/z=286.1; found:286.0.

Step 3. 3-Ethyl-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazin-5-amine

3-Ethyl-5-nitro-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazine (10 mg,0.3 mmol) was dissolved in methanol (10 mL) in a Parr bottle, degassedwith nitrogen, and palladium (10% on carbon) (10 mg) was added. Thereaction vessel was pressurized to 50 PSI with hydrogen and shaken for 2h. The reaction mixture was filtered and concentrated to give crude3-ethyl-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazin-5-amine (0.005 g,40%). LCMS calculated for C₁₅H₁₈N₃O (M+H)⁺: m/z=256.1; found: 256.0.

Step 4.4-Ethyl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one

Triphosgene (40 mg, 0.1 mmol) was added to a solution of3-ethyl-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazin-5-amine (80 mg, 0.3mmol) in tetrahydrofuran (5 mL) and N,N-diisopropylethylamine (0.1 mL).The reaction was stirred at room temperature for 1 h and was thenpartitioned between water and ethyl acetate. The organic layer waswashed with brine, dried over magnesium sulfate, filtered, andconcentrated to give crude4-ethyl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one(0.060 g. 60%). LCMS calculated for C₁₆H₁₆N₃O₂ (M+H)⁺: m/z=282.1; found:282.0.

Step 5.7-Bromo-4-ethyl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one

N-Bromosuccinimide (70 mg, 0.4 mmol) was added to a solution of4-ethyl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one(80 mg, 0.4 mmol) in acetonitrile (5 mL) and acetic acid (10 mL) cooledto 0° C. The reaction was stirred for 30 min, was concentrated to removeresidual acetic acid, and the resulting residue was dissolved in ethylacetate. The organic layer was washed with saturated aqueous sodiumbicarbonate, washed with brine, dried over magnesium sulfate, filtered,and concentrated to give crude7-bromo-4-ethyl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one(0.07 g. 80%). LCMS calculated for C₁₆H₁₅BrN₃O₂(M+H)⁺: m/z=360.1, 362.1;found: 359.8, 361.8.

Step 6.7-(3,5-Dimethylisoxazol-4-yl)-4-ethyl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one2,2,2-trifluoroacetate

7-Bromo-4-ethyl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one(50 mg, 0.1 mmol) was combined in 1,4-dioxane (6 mL) with potassium(3,5-dimethylisoxazol-4-yl)(trifluoro)borate (42 mg, 0.21 mmol) andpotassium carbonate (40 mg, 0.3 mmol) in water (3 mL) and was degassedwith nitrogen. The catalyst[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1) (20 mg, 0.02 mmol) was added and the mixture wasstirred at 100° C. for 18 h. The reaction mixture was allowed to cool toroom temperature and was then partitioned between ethyl acetate andwater. The organic layer was washed with brine, dried over magnesiumsulfate, and concentrated to give the crude product. The product waspurified on prep HPLC using a C-18 column eluting a water:acetonitrilegradient buffered to pH 2 with TFA to give7-(3,5-dimethylisoxazol-4-yl)-4-ethyl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-oneas a white solid (0.005 g, 10%). LCMS calculated for C₂₁H₂₁N₄O₃ (M+H)⁺:m/z=377.1; found: 377.0. ¹H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H),8.58-8.47 (m, 1H), 7.75 (td, J 7.7, 1.8 Hz, 1H), 7.28 (dd, J 6.6, 4.8Hz, 1H), 7.13 (d, J 8.0 Hz, 1H), 6.79 (d, J 8.0 Hz, 1H), 6.71 (d, J 8.0Hz, 1H), 4.84 (d, J 11.2 Hz, 1H), 4.29 (d, J 11.2 Hz, 1H), 2.71-2.51 (m,1H), 2.37-2.21 (m, 1H), 2.16 (s, 3H), 1.98 (s, 3H), 0.98 (t, J 7.4 Hz,3H).

Example 717-(3,5-Dimethylisoxazol-4-yl)-N-methyl-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-4-carboxamide2,2,2-trifluoroacetate

Step 1.5-Nitro-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazine-3-carbonitrile

Potassium cyanide (500 mg, 7 mmol) was added to a solution of5-nitro-3-pyridin-2-yl-2H-1,4-benzoxazine (1 g, 4 mmol) (Example 70,Step 1), in acetonitrile (20 mL), and was stirred overnight at roomtemperature. The reaction was partitioned between ethyl acetate andwater, and the organic layer was washed with brine, dried over magnesiumsulfate, filtered, and concentrated to give the crude product. Theproduct was crystallized from methylene chloride to give5-nitro-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazine-3-carbonitrile asa dark yellow powder (0.60 g. 60%). LCMS calculated for C₁₄H₁₁N₄O₃(M+H)⁺: m/z=283.1; found: 282.9.

Step 2.5-Nitro-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazine-3-carboxylic acid

5-Nitro-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazine-3-carbonitrile (80mg, 0.3 mmol) was dissolved in concentrated hydrochloric acid (3 mL, 100mmol) and heated to 100° C. for 2 h. The reaction was allowed to cool toroom temperature, diluted with water, and the pH was adjusted to pH 7with sodium bicarbonate. The neutralized solution was then extractedwith ethyl acetate. The combined organic layers were washed with brine,dried over magnesium sulfate, and concentrated to give crude5-nitro-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazine-3-carboxylic acidas a solid (0.025 g. 30%). LCMS calculated for C₁₄H₁₂N₃O₅(M+H)⁺:m/z=302.1; found: 301.9.

Step 3.N-Methyl-5-nitro-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazine-3-carboxamide

5-Nitro-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazine-3-carboxylic acid(0.044 g. 0.15 mmol) in N,N-dimethylformamide (3 mL) was combined withN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate [Oakwood #: 023926] (160 mg, 0.42 mmol) andN,N-diisopropylethylamine (100 μL, 0.6 mmol) at room temperature. 3.0 Mmethylamine in ethanol (0.2 mL, 0.6 mmol) was added, and the resultingmixture was stirred for 1 h, at which time the mixture was partitionedbetween water and ethyl acetate. The organic layer was washed with 1 NHCl, washed with brine, dried over magnesium sulfate, filtered, andconcentrated to give crudeN-methyl-5-nitro-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazine-3-carboxamidesolid (0.020 g. 30%). LCMS calculated for C₁₅H₁₅N₄O₄ (M+H)⁺: m/z=315.1;found: 315.0.

Step 4.5-Amino-N-methyl-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazine-3-carboxamide

N-Methyl-5-nitro-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazine-3-carboxamide(25 mg, 0.080 mmol) was dissolved in methanol (5 mL) in a Parr bottleand degassed with nitrogen, followed by addition of palladium (10% oncarbon) (5 mg, 0.05 mmol). The reaction vessel was charged to 50 PSIhydrogen and shaken for 2 h. The reaction mixture was filtered andconcentrated in vacuo to give crude5-amino-N-methyl-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazine-3-carboxamide(0.005 g. 100%). LCMS calculated for C₁₅H₁₇N₄O₂ (M+H)⁺: m/z=285.1;found: 285.0.

Step 5.N-Methyl-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-4-carboxamide

Triphosgene (10 mg, 0.04 mmol) was added to a solution of5-amino-N-methyl-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazine-3-carboxamide(30 mg, 0.1 mmol) in tetrahydrofuran (3 mL) andN,N-diisopropylethylamine (40 μL, 0.2 mmol) at room temperature and wasstirred for 1 h. The reaction mixture was then partitioned between ethylacetate and water, and the organic layer was washed with brine, driedover magnesium sulfate, and concentrated to give crudeN-methyl-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-4-carboxamideas a semisolid (0.031 g, 100%). LCMS calculated for C₁₆H₁₅N₄O₃ (M+H)⁺:m/z=311.1; found: 311.1.

Step 6. 7-Bromo-N-methyl-2-oxo-4-pyridin-2-yl-,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-4-carboxamide

N-Methyl-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-4-carboxamide(20 mg, 0. 1 mmol) was dissolved in acetonitrile (3 mL) and acetic acid(2 mL), and cooled to 0° C., followed by addition of N-bromosuccinimide(20 mg, 0.1 mmol). The reaction mixture was stirred for 1 h and was thenconcentrated to give a crude residue. The residue was dissolved in ethylacetate, washed with saturated aqueous sodium bicarbonate, washed withbrine, dried over magnesium sulfate, filtered, and concentrated to givecrude7-bromo-N-methyl-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-4-carboxamide(0.020 g, 50%). LCMS calculated for C₁₆H₁₄BrN₄O₃(M+H)⁺: m/z=389.1,391.1; found: 388.9, 390.9.

Step 7.7-(3,5-Dimethylisoxazol-4-yl)-N-methyl-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-4-carboxamide2,2,2-trifluoroacetate

7-Bromo-N-methyl-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-4-carboxamide(20 mg, 0.05 mmol) was combined with 1,4-dioxane (2 mL), potassium(3,5-dimethylisoxazol-4-yl)(trifluoro)borate (16 mg, 0.077 mmol) andpotassium carbonate (10 mg, 0.1 mmol) in water (1 mL, 60 mmol) and wasdegassed with nitrogen. The catalyst[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1) (7 mg, 0.008 mmol) was added, and the reactionmixture was stirred at 110° C. for 5 h. The reaction mixture was allowedto cool to room temperature and was then partitioned between ethylacetate and water. The organic layer was washed with brine, dried overmagnesium sulfate, and was concentrated to give crude product. Theproduct was purified on prep HPLC on a C-18 column eluting awater:acetonitrile gradient buffered at pH 2 with TFA to give7-(3,5-dimethylisoxazol-4-yl)-N-methyl-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-4-carboxamideas an off white solid (0.007 g, 30%). LCMS calculated for C₂₁H₂₀N₅O₄(M+H)⁺: m/z=406.1; found: 405.9. ¹H NMR (400 MHz, DMSO-d₆) δ 11.03 (s,1H), 8.57-8.45 (m, 1H), 8.19 (d, J=4.7 Hz, 1H), 7.82 (td, J=7.8, 1.8 Hz,1H), 7.48 (d, J=8.0 Hz, 1H), 7.36 (ddd, J=7.6, 4.8, 1.0 Hz, 1H), 6.83(d, J=8.0 Hz, 1H), 6.74 (d, J=8.0 Hz, 1H), 4.73 (s, 2H), 2.72-2.60 (m,3H), 2.22 (s, 3H), 2.04 (s, 3H).

Example 72N-{[7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]methyl}acetamide2,2,2-trifluoroacetate

Step 1.1-(5-Nitro-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazin-3-yl)methanamine

1.0 M Diisobutylaluminum hydride in toluene (200 μL, 0.2 mmol) was addeddrop-wise to a solution of5-nitro-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazine-3-carbonitrile (50mg, 0.2 mmol) (Example 71, Step 1), in toluene (5 mL) at roomtemperature. The reaction mixture was stirred for 10 min, then quenchedwith methanol. The resulting mixture was partitioned between ethylacetate and saturated aqueous sodium bicarbonate. The organic layer waswashed with brine, dried over magnesium sulfate, filtered, andconcentrated to give crude1-(5-nitro-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazin-3-yl)methanaminesolid (0.05 g. 100%). LCMS calculated for C₁₄H₁₅N₄O₃ (M+H)⁺: m/z=287.1;found: 287.1.

Step 2.N-[(5-Nitro-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazin-3-yl)methyl]acetamide

Acetyl chloride (15 μL, 0.21 mmol) was added to a mixture of1-(5-nitro-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazin-3-yl)methanamine(50 mg, 0.2 mmol) in methylene chloride (3 mL),N,N-diisopropylethylamine (60 μL) and was stirred at room temperaturefor 1 h. The reaction mixture was then partitioned between ethyl acetateand water. The organic layer was washed with brine, dried over magnesiumsulfate, filtered, and concentrated to give crudeN-[(5-nitro-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazin-3-yl)methyl]acetamide(0.040 g. 70%). LCMS calculated for C₁₆H₁₇N₄O₄ (M+H)⁺: m/z=329.1; found:329.0.

Step 3.N-[(5-Amino-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazin-3-yl)methyl]acetamide

N-[(5-Nitro-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazin-3-yl)methyl]acetamide(0.040 g. 0.122 mmol) was dissolved in ethanol (5 mL) in a Parr bottleand degassed with nitrogen, followed by addition of palladium (10% oncarbon) (10 mg, 0.09 mmol) catalyst. The reaction vessel was charged to50 PSI with hydrogen, and shaken for 2 h. The mixture was then filteredand concentrated to give crudeN-[(5-amino-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazin-3-yl)methyl]acetamide(0.040 g, 80%). LCMS calculated for C₁₆H₁₉N₄O₂ (M+H)⁺: m/z=299.1; found:299.0.

Step 4.N-[(2-Oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl)methyl]acetamide

Triphosgene (20 mg, 0.07 mmol) was added to a mixture ofN-[(5-amino-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazin-3-yl)methyl]acetamide(50 mg, 0.2 mmol), tetrahydrofuran (5 mL) and N,N-diisopropylethylamine(60 μL) at room temperature. The reaction was stirred for 1 h thenpartitioned between ethyl acetate and water. The organic layer waswashed with brine, dried over magnesium sulfate, filtered, andconcentrated to give crudeN-[(2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl)methyl]acetamide(0.040 g. 70%). LCMS calculated for C₁₇H₁₇N₄O₃ (M+H)⁺: m/z=325.1; found:325.1.

Step 5.N-[(7-Bromo-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl)methyl]acetamide

N-Bromosuccinimide (40 mg, 0.2 mmol) was added to a mixture ofN-[(2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl)methyl]acetamidein acetonitrile (5 mL) and acetic acid (3 mL), and cooled to 0° C. Thereaction was stirred for 1 h, concentrated to remove residual aceticacid, and partitioned between ethyl acetate and saturated aqueous sodiumbicarbonate. The organic layer was washed with brine, dried overmagnesium sulfate, filtered, and concentrated to give crudeN-[(7-bromo-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl)methyl]acetamide(0.040 g. 60%). LCMS calculated for C₁₇H₁₆BrN₄O₃(M+H)⁺: m/z=403.1,405.1; found: 402.9, 405.0.

Step 6.N-{[7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]methyl}acetamide2,2,2-trifluoroacetate

N-[(7-Bromo-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl)methyl]acetamide(20 mg, 0.05 mmol) was combined in 1,4-dioxane (2 mL) with potassium(3,5-dimethylisoxazol-4-yl)(trifluoro)borate (16 mg, 0.077 mmol) andpotassium carbonate (10 mg, 0.1 mmol) in water (1 mL) and was degassedwith nitrogen. The catalyst[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1) (7 mg, 0.008 mmol) was added and the reaction wasstirred at 110° C. for 5 h. The reaction mixture was allowed to cool toroom temperature, at which time it was partitioned between ethyl acetateand water. The organic layer was washed with brine, dried over magnesiumsulfate, and was concentrated to give crude product. The product waspurified by prep HPLC on a C-18 column eluting a water:acetonitrilegradient buffered at pH 2 with TFA to giveN-{[7-(3,5-dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]methyl}acetamideas an off white solid (0.010 g, 50%). LCMS calculated for C₂₂H₂₂N₅O₄(M+H)⁺: m/z=420.1; found: 420.1.

Example 734-(Aminomethyl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-onebis(2,2,2-trifluoroacetate)

N-{[7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]methyl}acetamide(10 mg, 0.02 mmol) was dissolved in tetrahydrofuran (1 mL) andconcentrated hydrochloric acid (200 μL, 6 mmol) in water (800 μL). Thereaction was heated to 100° C. for 4 h and was then purified withoutworkup by prep HPLC on a C-18 column eluting a water:acetonitrilegradient buffered at pH 2 with TFA to give4-(aminomethyl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-oneas off white solid (0.0045 g, 40%). LCMS calculated for C₂₀H₂₀N₅O₃(M+H)⁺: m/z=378.1; found: 378.1. ¹H NMR (400 MHz, DMSO-d₆) δ 11.40 (s,1H), 8.68-8.58 (m, 1H), 8.20 (bs, 2H), 7.84 (td, J=7.8, 1.8 Hz, 1H),7.48-7.37 (m, 1H), 7.16 (d, J=8.0 Hz, 1H), 6.91 (d, J=8.0 Hz, 1H), 6.84(d, J=8.0 Hz, 1H), 4.73 (d, 1H), 4.41 (d, 1H), 4.12-3.97 (m, 1H),3.75-3.58 (m, 1H), 2.18 (s, 3H), 2.00 (s, 3H).

Example 747-(3,5-Dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-4-carboxamide2,2,2-trifluoroacetate

Step 1.5-Nitro-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazine-3-carboxamide

5-Nitro-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazine-3-carbonitrile(100 mg, 0.4 mmol) was added to a vigorously stirring mixture ofaluminum oxide (100 mg, 1 mmol) and methanesulfonic acid (2 mL, 30 mmol)at room temperature. The reaction mixture was then heated to 120° C. for20 min, allowed to cool to room temperature, and partitioned betweenwater and ethyl acetate. The organic layer was washed with brine, driedover magnesium sulfate, filtered, and concentrated to give crudeproduct. The product was purified by FCC on silica gel eluting ahexane:ethyl acetate gradient to give5-nitro-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazine-3-carboxamide asclear oil (0.040 g. 40%). LCMS calculated for C₁₄H₁₃N₄O₄ (M+H)⁺:m/z=301.1; found: 301.1.

Step 2.5-Amino-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazine-3-carboxamide

5-Nitro-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazine-3-carboxamide(0.040 g, 0.13 mmol) was dissolved in methanol (5 mL) in a Parr bottleand degassed with nitrogen, followed by addition of palladium (10% oncarbon) (20 mg, 0.2 mmol). The reaction vessel was charged to 50 PSIwith hydrogen and shaken for 2 h. The reaction mixture was then filteredand concentrated to give crude5-amino-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazine-3-carboxamide as aglass (0.040 g. 100%). LCMS calculated for C₁₄H₁₅N₄O₂ (M+H)⁺: m/z=271.1;found: 271.1.

Step 3.2-Oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-4-carboxamide

Triphosgene (20 mg, 0.07 mmol) was added to a solution of5-amino-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazine-3-carboxamide (40mg, 0.2 mmol) in tetrahydrofuran (5 mL) and N,N-diisopropylethylamine(60 μL, 0.3 mmol) at room temperature. The reaction was stirred for 1 hand then partitioned between ethyl acetate and water. The combinedorganic layer was washed with brine, dried over magnesium sulfate,filtered, and concentrated to give crude2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-4-carboxamide(0.040 g. 80%). LCMS calculated for C₁₅H₁₃N₄O₃ (M+H)⁺: m/z=297.1; found:297.1.

Step 4.7-Bromo-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-4-carboxamide

N-Bromosuccinimide (40 mg, 0.2 mmol) was added to a solution of2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-4-carboxamide,acetonitrile (5 mL) and acetic acid (3 mL) and cooled to 0° C. Thereaction mixture was stirred for 1 h and then concentrated to removeresidual acetic acid. The resulting residue was partitioned betweenethyl acetate and saturated aqueous sodium bicarbonate. The organiclayer was washed with brine, dried over magnesium sulfate, filtered, andconcentrated to give crude7-bromo-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-4-carboxamide(0.040 g. 60%). LCMS calculated for C₁₅H₁₂BrN₄O₃(M+H)⁺: m/z=375.1,377.1; found: 375.0, 376.9.

Step 5.7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-4-carboxamide2,2,2-trifluoroacetate

7-Bromo-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-4-carboxamide(20 mg, 0.05 mmol) was combined in 1,4-dioxane (2 mL) with potassium(3,5-dimethylisoxazol-4-yl)(trifluoro)borate (16 mg, 0.077 mmol) andpotassium carbonate (10 mg, 0.1 mmol) in water (1 mL) was degassed withnitrogen. The catalyst[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (1:1) (7 mg, 0.008 mmol) was added and degassedwith nitrogen. The reaction was stirred at 110° C. for 5 h, allowed tocool to room temperature, and partitioned between ethyl acetate andwater. The organic layer was washed with brine, dried over magnesiumsulfate, and concentrated to give crude product. The product waspurified by prep HPLC on a C-18 column eluting a water:acetonitrilegradient buffered to pH 2 to give7-(3,5-dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-4-carboxamideas an off white solid (0.010 g. 50%). LCMS calculated for C₂₀H₁₈N₅O₄(M+H)⁺: m/z=392.1; found: 392.1. ¹H NMR (400 MHz, DMSO-d₆) δ 11.04 (s,1H), 8.56-8.48 (m, 1H), 7.83 (td, J=7.8, 1.8 Hz, 1H), 7.78-7.70 (m, 2H),7.52 (d, J=8.1 Hz, 1H), 7.42-7.32 (m, 1H), 6.83 (d, J=8.0 Hz, 1H), 6.74(d, J=8.0 Hz, 1H), 4.76 (d, J=11.2 Hz, 1H), 4.71 (d, 1H), 2.23 (s, 3H),2.05 (s, 3H).

Example 797-(3,5-dimethylisoxazol-4-yl)-4-[1-(methylsulfonyl)piperidin-2-yl]-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one

The amine7-(3,5-dimethylisoxazol-4-yl)-4-piperidin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one(0.05 g, 0.14 mmol) (Example 63) was dissolved in methylene chloride(2.0 mL) and N,N-diisopropylethylamine (0.049 mL, 0.28 mmol) at rt undernitrogen. Methanesulfonyl chloride (0.010 mL, 0.14 mmol) was added andthe reaction was stirred at rt. After stirring for 1 h, the reaction wasdissolved in ethyl acetate and washed with water, brine, dried overmagnesium sulfate and concentrated to give crude product as a dark oil.The product was purified by prep HPLC on a C-18 column elutingwater:acetonitrile gradient buffered pH 2 with TFA to give7-(3,5-dimethylisoxazol-4-yl)-4-[1-(methylsulfonyl)piperidin-2-yl]-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-oneas two fractions:

Example 79, Peak 1 as a solid residue (0.015 g, 26%). LCMS calculatedfor C₂₀H₂₅N₄O₅S (M+H)⁺: m/z=433.1; found: 433.2. ¹H NMR (400 MHz,DMSO-d₆) δ 10.69 (s, 1H), 6.78 (d, J=8.0 Hz, 1H), 6.65 (d, J=8.0 Hz,1H), 4.89-4.65 (m, 3H), 4.4-3.9 (m, 2H), 3.62 (m, 1H), 2.28 (s, 3H),2.11 (s, 3H), 1.96 (m, 1H), 1.82 (s, 3H), 1.73-1.51 (m, 3H), 1.41 (m,1H), 1.1 (m, 1H).

Example 79, Peak 2 as a solid residue (0.010 g, 18%). LCMS calculatedfor C₂₀H₂₅N₄O₄S (M+H)⁺: m/z=433.1; found: 433.2.

Examples 75-87

The experimental procedures used to prepare the compounds of Examples 75to 87 are summarized in Table 3 below.

TABLE 3

Ex. No. Name R¹ R⁷ Cy³ Salt Proc.* 75 7-(3,5-dimethylisoxazol-4-yl)-5-methyl-4-pyridin-2-yl-4,5- dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one Me H

13 76 7-(3,5-dimethylisoxazol-4-yl)- N-methyl-2-oxo-4-pyridin-2-yl-1,2,4,5- tetrahydroimidazo[1,5,4- de][1,4]benzoxazine-5- carboxamide2,2,2-

H

TFA 24 trifluoroacetate 77 7-(3,5-dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-1,2,4,5- tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-5- carboxamide 2,2,2- trifluoroacetate

H

TFA 24 78 7-(3,5-dimethylisoxazol-4-yl)- 4-(5-fluoropyridin-3-yl)-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazin-2(III)-one H H

5 79 7-(3,5-dimethylisoxazol-4-yl)- 4-[1-2 (methylsulfonyl)piperidin-2-yl]-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazin-2(1H)-one H H

79 80 2-[7-(3,5-dimethylisoxazol-4- yl)-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4- de][1,4]benzoxazin-4-yl]-N-isopropylpiperidine-1- carboxamide H H

79 81 (4S)-7-(3,5-dimethylisoxazol- 4-yl)-9-(1-methyl-1H-pyrazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one 2,2,2-trifluoroacetate H

TFA 43 82 5-[(4S)-7-(3,5- dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-1,2,4,5- tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-9-yl]-N,N- dimethylpyridine-2- carboxamide 2,2,2-bis(trifluoroacetate) H

2TFA 43 83 tert-butyl 4-[(4S)-7-(3,5- dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-1,2,4,5- tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-9-yl]-3,6- dihydropyridine-1(2H)- carboxylate 2,2,2-trifluoroacetate H

TFA 43 84 (4S)-7-(3,5-dimethylisoxazol- 4-yl)-4-pyridin-2-yl-9-pyrimidin-5-yl-4,5- dihydroimidazo[1,5,4- de][1,4]benzoxazin-2(1H)-one2,2,2-trifluoroacetate H

TFA 43 85 (4S)-7-(3,5-dimethylisoxazol- 4-yl)-9-(1-methyl-1H-pyrazol-5-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one 2,2,2-trifluoroacetate H

TFA 43 86 ethyl (2E)-3-[(4S)-7-(3,5- dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-1,3,4,5- tetrahydroimidazo[1,5,4- de][1,4]benzoxazin-9-yl]acrylate 2,2,2- H

TFA 43 trifluoroacetate 87 (4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-9- (1,2,3,6-tetrahydropyridin-4-yl)-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazin-2(1H)-onebis(2,2,2-trifluoroacetate) H

2TFA 43 *Synthesized according to the experimental procedure of Examplenumber listed.

Example 88(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-2-vinyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine

(4S)-2-Chloro-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine(277 mg, 0.755 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane(0.19 mL, 1.1 mmol) [Aldrich, cat. #633348], and potassium phosphate(0.3 g, 2 mmol) [Aldrich, cat. # P5629], were dissolved in water (2.4mL) and 1,4-dioxane (10 mL). The reaction mixture was deoxygenated withnitrogen anddicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (0.03 g, 0.04 mmol) [Aldrich, cat. #741825] was added. Theresulting mixture was deoxygenated with nitrogen and heated at 80° C.for 3 h. The reaction mixture was then allowed to cool to roomtemperature. Ethyl acetate was added, and the mixture was washed withwater and brine, then dried over sodium sulfate and concentrated. Theresulting residue was purified by flash chromatography eluting ethylacetate in hexanes (75-100%, ethyl acetate containing 20% MeOH) toafford the desired product (0.21 g, 78%). LCMS for C₂₁H₁₉O₂N₄ (M+H)+:calculated m/z=359.2; found 359.3; ¹H NMR (400 MHz, CD₃OD) δ 8.61-8.53(m, 1H), 7.74 (m, 1H), 7.39 (d, J=8.4 Hz, 1H), 7.34 (dd, J=7.7, 4.8 Hz,1H), 7.14 (d, J=8.4 Hz, 1H), 6.75 (d, J=4.1 Hz, 1H), 6.69 (d, J=11.4 Hz,1H), 6.34 (dd, J=17.5, 1.0 Hz, 1H), 6.09 (dd, J=2.5 Hz, 2H), 5.68 (dd,J=11.4, 1.0 Hz, 1H), 4.96 (dd, J=11.6, 2.1 Hz, 1H), 4.64 (dd, J=11.6,3.1 Hz, 1H), 2.29 (s, 3H), 2.15 (s, 3H).

Example 89(1R)-1-[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]ethane-1,2-diol

(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-2-vinyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine(40 mg, 0.1 mmol) was dissolved in tert-butyl alcohol (4 mL) and water(4 mL). To the resulting solution, the mixture of A-D mix β (300 mg, 0.7mmol) [Aldrich, cat. #392766] was added at room temperature. Theresulting mixture was stirred overnight. Saturated aqueous sodiumsulfite (2 mL) was added and the suspension was stirred for 15 min atroom temperature. The mixture was then extracted with dichloromethane.The organic extracts were combined, washed with brine, dried over sodiumsulfate, filtered, and concentrated. Purification by preparative LCMS(XBridge C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% ammonium hydroxide, at flow rate of 60 mL/min) affordedthe desired product (0.021 g, 50%). LCMS for C₂₁H₂₁O₄N₄ (M+H)+:calculated m/z=393.2; found 393.2.

Example 901-[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]ethanol

Step 1.(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine-2-carbaldehyde

(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-2-vinyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine(0.05 g, 0.1 mmol) was dissolved in tetrahydrofuran (1.7 mL). Theresulting solution was cooled to 0° C., then a solution of 0.16 M osmiumtetraoxide in water (0.3 mL, 0.04 mmol) [Aldrich, cat. #251755] andsodium metaperiodate (140 mg, 0.66 mmol) [Aldrich, cat. # S 1878] inwater (0.1 mL) were added. The reaction was allowed to warm to roomtemperature and stirred for 1 h. The reaction was quenched withsaturated aqueous sodium sulfite (10 mL) for 10 min at room temperature.The mixture was filtered through a Celite plug and the plug was rinsedwith dichloromethane. The organic layer was concentrated under vacuum.The resulting residue was purified by flash chromatography eluctingethyl acetate in hexanes (75-100%, ethyl acetate containing 20% MeOH) toafford the desired product (0.053 g, 100%). LCMS for C₂₀H₁₇O₃N₄ (M+H)+:calculated m/z=361.1; found 361.2.

Step 2.1-[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]ethanol

To the solution of(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine-2-carbaldehyde(8 mg, 0.02 mmol) in tetrahydrofuran (1 mL) at 0° C., 3.0 Mmethylmagnesium chloride in THF (0.01 mL, 0.04 mmol) [Aldrich, cat.#189901] was added dropwise. After continued stirring for 30 min at 0°C., the reaction was quenched by adding saturated aqueous ammoniumchloride (0.5 mL) dropwise. The resulting mixture was diluted with ethylacetate/brine (3:1), and the organic layer was separated. The aqueouslayer was extracted with ethyl acetate. The combined organic layers weredried over sodium sulfate, filtered, and concentrated under vacuum.Purification by preparative LCMS (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% ammonium hydroxide, atflow rate of 60 mL/min) afforded the desired product as a mixture ofdiastereomers (4 mg, 50%). LCMS for C₂₁H₂₁O₃N₄ (M+H)+: calculatedm/z=377.2, found 377.1.

Example 91(4S)-7-(3,5-Dimethylisoxazol-4-yl)-N,N-dimethyl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine-2-carboxamide

Example 92(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine

Example 93 tert-Butyl(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine-2-carboxylate

(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine-2-carbaldehyde(15 mg, 0.042 mmol) and dimethylamine hydrochloride (0.0041 g, 0.050mmol) [Aldrich, cat. #126365] were dissolved in acetonitrile (1.5 mL) atroom temperature. To the resulting mixture, copper(II) sulfatepentahydrate (0.0005 g, 0.002 mmol) [Aldrich, cat. #209198], calciumcarbonate (0.0046 g, 0.046 mmol) [Aldrich, cat. #C6763] and 6.0 Mtert-butyl hydroperoxide in decane (0.0076 mL, 0.046 mmol) [Aldrich,cat. #416665] were added. The reaction vessel was capped, degassed, andallowed to stir at 40° C. for 10 hours. After filtration through Celite,the solution was concentrated and the resulting residue was purified bypreparative LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of60 mL/min) afforded the following three compounds:

Example 91 (7.2 mg, 43%) LCMS for C₂₂H₂₂O₃N₅ (M+H)+: calculatedm/z=404.2; found 404.2. ¹H NMR (400 MHz, CD₃OD) δ 8.49 (d, J=4.6 Hz,1H), 7.81-7.71 (m, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.37-7.28 (m, 1H), 7.18(d, J=8.4 Hz, 1H), 7.03 (d, J=7.9 Hz, 2H), 6.15 (d, J=3.6 Hz, 1H), 5.48(s, 1H), 4.79 (dd, J=11.8, 3.9 Hz, 2H), 4.70 (dd, J=11.7, 3.2 Hz, 1H),3.38 (s, 3H), 2.94 (s, 3H), 2.30 (s, 3H), 2.15 (s, 3H).

Example 92 (2.4 mg, 17%) LCMS for C₁₉H₁₇O₂N₄ (M+H)+: calculatedm/z=333.1; found 333.2 ¹H NMR (400 MHz, CD₃OD) δ 8.61 (d, J=3.9 Hz, 1H),8.23 (s, 1H), 7.83 (dd, J=7.8 Hz, 1H), 7.48-7.36 (m, 2H), 7.14 (d, J=7.8Hz, 2H), 7.06 (d, J=7.9 Hz, 2H), 5.94 (s, 1H), 4.82-4.74 (m, 2H),4.74-4.67 (m, 2H), 2.32 (s, 3H), 2.18 (s, 3H).

Example 93 (3.2 mg, 18%) LCMS for C₂₄H₂₅O₄N₄ (M+H)+: calculatedm/z=433.2, found 433.2; ¹H NMR (400 MHz, CD₃OD) δ 8.52 (d, J=4.8 Hz,1H), 7.77-7.67 (m, 1H), 7.53 (d, J=8.5 Hz, 1H), 7.38-7.29 (m, 1H), 7.24(d, J=8.5 Hz, 1H), 6.71 (d, J=7.9 Hz, 1H), 6.40 (s, 1H), 5.00 (dd,J=11.7, 3.1 Hz, 1H), 4.69 (dd, J=11.8, 3.1 Hz, 1H), 2.28 (s, 3H), 2.14(s, 3H), 1.47 (s, 9H).

Example 94(4S)-7-(3,5-Dimethylisoxazol-4-yl)-2-(morpholin-4-ylcarbonyl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine

The title compound was prepared by methods analogous to Example 91,using morpholine [Aldrich, cat. #252360] as the nucleophile.Purification by preparative LCMS (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% ammonium hydroxide, atflow rate of 60 mL/min) afforded the title compound. LCMS for C₂₄H₂₄O₄N₅(M+H)+: calculated m/z=446.2, found 446.1; ¹H NMR (400 MHz, CD₃OD) δ8.51 (d, J=4.2 Hz, 1H), 7.78 (m, 1H), 7.47 (d, J=8.4 Hz, 1H), 7.34 (dd,J=7.1, 5.4 Hz, 1H), 7.20 (d, J=8.4 Hz, 1H), 7.06 (d, J=7.9 Hz, 1H), 6.20(m, 1H), 4.81 (dd, J=11.8, 3.7 Hz, 1H), 4.72 (dd, J=11.7, 3.3 Hz, 1H),4.12 (s, 2H), 3.83-3.69 (m, 2H), 3.59 (t, J=8.1 Hz, 4H), 2.16 (s, 3H),2.04 (s, 3H).

Example 95(4S)-7-(3,5-Dimethylisoxazol-4-yl)-N-methyl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine-2-carboxamide

The title compound was prepared by methods analogous to Example 91,using 2.0 M methylamine in tetrahydrofuran [Aldrich, cat. #395056] asthe nucleophile. Purification by preparative LCMS (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% ammoniumhydroxide, at flow rate of 60 mL/min) afforded the title compound. LCMSfor C₂₁H₂₀O₃N₅ (M+H)+: calculated m/z=390.2, found 390.2; ¹H NMR (400MHz, CD₃OD) δ 8.49 (d, J=4.8 Hz, 1H), 7.69 (m, 1H), 7.49 (d, J=8.5 Hz,1H), 7.28 (dd, J=6.9, 4.9 Hz, 1H), 7.19 (d, J=8.5 Hz, 1H), 6.64 (d,J=7.9 Hz, 1H), 6.56-6.50 (m, 1H), 4.96 (dd, J=11.7, 3.1 Hz, 1H), 4.65(dd, J=11.7, 3.0 Hz, 1H), 2.88 (s, 1H), 2.27 (s, 3H), 2.13 (s, 3H).

Example 96(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine-2-carboxamide

The title compound was prepared by methods analogous to Example 91,using hydroxylamine hydrochloride [Aldrich, cat. #159417] as thenucleophile. Purification by preparative LCMS (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% ammoniumhydroxide, at flow rate of 60 mL/min) afforded the title compound. LCMSfor C₂₀H₁₈O₃N₅ (M+H)+: calculated m/z=376.1, found 376.2; ¹H NMR (400MHz, CD₃OD) δ 8.49 (d, J=4.8 Hz, 1H), 8.20 (s, 1H), 7.69 (m, 1H), 7.43(d, J=8.5 Hz, 1H), 7.28 (dd, J=6.9, 4.9 Hz, 1H), 7.19 (d, J=8.5 Hz, 1H),6.54 (d, J=7.9 Hz, 1H), 6.33 (m, 1H), 4.96 (dd, J=11.7, 3.1 Hz, 1H),4.65 (dd, J=11.7, 3.0 Hz, 1H), 2.27 (s, 3H), 2.13 (s, 3H).

Example 97 tert-Butyl4-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]-3,6-dihydropyridine-1(2H)-carboxylate

(4S)-2-Chloro-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine(80 mg, 0.2 mmol), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate(100 mg, 0.4 mmol) [Aldrich, cat. # CDS015890], and potassium phosphate(0.09 g, 0.4 mmol) [Aldrich, cat. # P5629] were suspended in 1,4-dioxane(3 mL) and water (0.70 mL). The resulting mixture was degassed withnitrogen for 10 min anddicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (0.008 g, 0.01 mmol) [Aldrich, cat. #741825] was added, followedby an additional 10 min of degassing. The reaction mixture was sealedand heated at 50° C. for 16 h. After cooling to room temperature, thereaction mixture was extracted with dichloromethane. The combinedorganic layers were washed with brine, dried over sodium sulfate,filtered, and concentrated under reduced pressure. The residue waspurified by flash chromatography eluting ethyl acetate in hexanes(75-100%) to afford the desired product (98 mg, 90%). LCMS forC₂₉H₃₂O₄N₅ (M+H)+: calculated m/z=514.2, found 514.2; ¹H NMR (300 MHz,CD₃OD) δ 8.54 (d, J=4.7 Hz, 1H), 7.72 (m, 2H), 7.44-7.27 (m, 2H), 7.10(d, J=8.4 Hz, 1H), 6.75 (d, J=8.1 Hz, 1H), 6.14 (s, 1H), 6.07 (d, J=2.8Hz, 1H), 4.78 (dd, J=11.6, 2.9 Hz, 1H), 4.59 (dd, J=11.6, 3.1 Hz, 1H),4.11-3.72 (m, 2H), 3.51 (d, J=16.0 Hz, 2H), 2.60 (s, 2H), 2.25 (s, 3H),2.10 (s, 3H), 1.42 (s, 9H).

Example 98 tert-Butyl3-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]-2,5-dihydro-1H-pyrrole-1-carboxylate

The title compound was prepared by methods analogous to Example 97,using tert-butyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate[Combi-Blocks, cat. # FM2879] as the Suzuki-coupling reagent. The crudeproduct was purified by flash chromatography with ethyl acetate inhexanes (75-100%) to afford the title compound. LCMS for C₂₈H₃₀O₄N₅(M+H)+: calculated m/z=500.2, found 500.4; ¹H NMR (400 MHz, CD₃OD) δ8.64-8.52 (m, 1H), 7.78-7.67 (m, 1H), 7.43 (d, J=8.4 Hz, 1H), 7.39-7.29(m, 1H), 7.16 (d, J=8.4 Hz, 1H), 6.70 (m, 1H), 6.30 (d, J=8.5 Hz, 1H),6.18 (s, 1H), 4.95 (d, J=11.6 Hz, 1H), 4.69 (s, 1H), 4.63 (dd, J=11.6,3.1 Hz, 1H), 4.57 (s, 1H), 4.32 (d, J=17.3 Hz, 1H), 4.21 (d, J=17.6 Hz,1H), 2.29 (s, 3H), 2.15 (s, 3H), 1.51 (s, 6H), 1.48 (s, 3H).

Example 99 tert-Butyl5-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]-3,6-dihydropyridine-1(2H)-carboxylate

The title compound was prepared by methods analogous to Example 97,using tert-butyl5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate[Anisyn, cat. # CT603191] as the Suzuki-coupling reagent. The crudeproduct was purified by flash chromatography eluting ethyl acetate inhexanes (75-100%) to afford the title compound. LCMS for C₂₉H₃₂O₄N₅(M+H)+: calculated m/z=514.2, found 514.2; ¹H NMR (400 MHz, CD₃OD) δ8.56 (m, 1H), 7.74 (dd, J=7.8, 1.7 Hz, 1H), 7.40 (d, J=8.4 Hz, 1H), 7.33(dd, J=6.9, 5.0 Hz, 1H), 7.12 (d, J=8.4 Hz, 1H), 6.79 (d, J=7.8 Hz, 1H),6.30 (s, 1H), 6.08 (t, J=2.8 Hz, 1H), 4.81 (dd, J=11.6, 2.9 Hz, 1H),4.61 (dd, J=11.6, 3.1 Hz, 1H), 4.39 (s, 2H), 4.14-4.02 (m, 2H), 3.50 (m,1H), 3.31 (m, 1H), 2.27 (s, 3H), 2.13 (s, 3H), 1.47 (s, 9H).

Example 100 tert-Butyl4-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperidine-1-carboxylate

(tert-Butyl4-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]-3,6-dihydropyridine-1(2H)-carboxylate(80 mg, 0.2 mmol) was dissolved in methanol (6 mL), and the mixture wasdegassed with nitrogen for 15 min, followed by addition of palladium oncarbon (30 mg, 0.02 mmol) [Aldrich, cat. #130108]. After threevacuum/nitrogen gas refilling cycles, 1 atm hydrogen gas was charged tothe mixture with a balloon. After stirring for 2 h at room temperature,the reaction mixture was filtered through Celite and the filter wassubsequently washed with methanol (30 mL). The combined organic layerswere concentrated under reduced pressure. The residue was purified byflash chromatography eluting ethyl acetate in hexanes (75-100%) toafford the desired product (48 mg, 60%). LCMS for C₂₉H₃₄O₄N₅ (M+H)+:calculated m/z=516.3, found 516.2; ¹H NMR (400 MHz, CD₃OD) δ 8.59-8.49(m, 1H), 7.73 (m, 1H), 7.36-7.28 (m, 2H), 7.06 (d, J=8.3 Hz, 1H), 6.78(d, J=7.9 Hz, 1H), 6.00 (m, 1H), 4.89 (dd, J=11.7, 3.1 Hz, 1H), 4.60(dd, J=11.6, 3.1 Hz, 1H), 4.16 (d, J=13.4 Hz, 1H), 4.04 (d, J=13.5 Hz,1H), 2.95 (ddd, J=11.8, 8.3, 3.6 Hz, 1H), 2.88-2.51 (m, 2H), 2.25 (s,3H), 2.11 (s, 3H), 2.06-1.94 (m, 1H), 1.92-1.66 (m, 2H), 1.44 (s, 9H).

Example 101A tert-Butyl3-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidine-1-carboxylate(Diastereoisomer 1) Example 101B tert-Butyl3-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidine-1-carboxylate(Diastereoisomer 2)

The title compounds were prepared by methods analogous to Example 99,using tert-butyl3-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]-2,5-dihydro-1H-pyrrole-1-carboxylateas the starting material. Purification by preparative LCMS (XBridge C18column, eluting with a gradient of acetonitrile/water containing 0.1%ammonium hydroxide, at flow rate of 60 mL/min) afforded the titlecompound as two diastereoisomers.

Diastereoisomer 1. Preparative LCMS Peak I. LCMS for C₂₈H₃₂O₄N₅ (M+H)⁺:calculated m/z=502.2; found 502.1; ¹H NMR (400 MHz, CD₃OD) δ 8.57 (s,1H), 7.78 (s, 1H), 7.37 (d, J=7.9 Hz, 2H), 7.11 (d, J=8.3 Hz, 1H),6.93-6.77 (m, 1H), 6.04 (s, 1H), 4.96 (d, J=12.8 Hz, 1H), 4.64 (dd,J=11.7, 2.9 Hz, 1H), 3.63 (d, J=5.0 Hz, 2H), 3.38 (m, 1H), 2.40 (m, 1H),2.29 (s, 3H), 2.15 (s, 3H), 1.45 (s, 3H), 1.39 (s, 6H).

Diastereoisomer 2. Preparative LCMS Peak II. LCMS for C₂₈H₃₂O₄N₅ (M+H)⁺:calculated m/z=502.2; found 502.1; ¹H NMR (400 MHz, CD₃OD) δ 8.57 (d,J=4.5 Hz, 1H), 7.76 (m, 1H), 7.42-7.29 (m, 2H), 7.11 (d, J=8.3 Hz, 1H),6.91-6.73 (m, 1H), 6.04 (s, 1H), 4.93 (dd, J=11.7, 2.0 Hz, 2H), 4.64 (d,J=10.5 Hz, 1H), 3.96-3.82 (m, 1H), 3.80-3.49 (m, 1H), 2.29 (s, 3H), 2.14(s, 3H), 2.11-1.82 (m, 2H), 1.47 (s, 9H).

Example 102 tert-Butyl3-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperidine-1-carboxylate

The title compound was prepared by methods analogous to Example 100,using tert-butyl5-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]-3,6-dihydropyridine-1(2H)-carboxylateas starting material. Purification by preparative LCMS (XBridge C18column, eluting with a gradient of acetonitrile/water containing 0.1%ammonium hydroxide, at flow rate of 60 mL/min) afforded the titlecompound. LCMS for C₂₉H₃₄O₄N₅ (M+H)⁺: calculated m/z=516.3, found 516.2.

Example 103(4S)-2-(1-Acetylpiperidin-4-yl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine

tert-Butyl4-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]-3,6-dihydropyridine-1(2H)-carboxylate(3 mg, 0.006 mmol) was dissolved in methanol (0.5 mL) at roomtemperature, followed by addition of 4.0 M hydrogen chloride in dioxane(0.5 mL, 2 mmol) [Aldrich, cat. #345547]. The resulting mixture wasstirred at room temperature for 10 min. The solvents were removed undera flow of nitrogen gas. Purification by preparative LCMS (XBridge C18column, eluting with a gradient of acetonitrile/water containing 0.1%ammonium hydroxide, at flow rate of 60 mL/min) afforded the titlecompound (1.8 mg, 70%). LCMS for C₂₄H₂₆O₂N₅ (M+H)+: calculatedm/z=416.2, found 416.2.

Examples 104-108

The experimental procedures used to prepare the compounds of Examples104 to 108 in Table 4 were analogous to those used for the synthesis ofthe Example compound 103.

TABLE 4

Example No. Name R 104 (4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-2-(1,2,3,6-tetra- hydropyridin-4-yl)-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine

105 (4S)-2-(2,5-dihydro-1H-pyrrol-3-yl)-7-(3,5-dimethylisoxazol-4-yl)-4- pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine

106A (4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-2-pyrrolidin-3-yl-4,5- dihydroimidazo[1,5,4-de][1,4]benzoxazine (diastereomer 1)

106B (4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-2-pyrrolidin-3-yl-4,5- dihydroimidazo[1,5,4-de][1,4]benzoxazine (diastereomer 2)

107 (4S)-7-(3,5-dimethylisoxazol-4-yl)- 4-pyridin-2-yl-2-(1,2,5,6-tetra-hydropyridin-3-yl)-4,5- dihydroimidazo[1,5,4-de][1,4] benzoxazine

108 (4S)-7-(3,5-dimethylisoxazol-4-yl)-2-piperidin-3-yl-4-pyridin-2-yl-4,5- dihydroimidazo[1,5,4-de][1,4]benzoxazine (mixture of diastereomers)

Example 109(4S)-2-(1-Acetylpiperidin-4-yl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine

To the solution of tert-butyl4-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperidine-1-carboxylate(8.8 mg, 0.017 mmol) in methanol (1 mL) was added 4.0 M hydrogenchloride in dioxane (1 ml) at room temperature. The resulting mixturewas stirred at room temperature for 10 min. The solvents were thenevaporated under a steam of nitrogen. Triethylamine (0.23 mL, 1.7 mmol)was added to the resulting residue, followed by acetyl chloride (0.029mL, 0.41 mmol). The mixture was then stirred under a stream of nitrogenfor 5 min at room temperature, followed by removal of solvents andresidual reagents. Purification by preparative LCMS (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% ammoniumhydroxide, at flow rate of 60 mL/min) afforded the title compound (6.3mg, 81%). LCMS for C₂₆H₂₈O₃N₅ (M+H)+: calculated m/z=458.2, found 458.2.

Examples 110-121

The experimental procedures used to prepare the compounds of Examples110 to 121 in Table 5 were analogous to those used for the synthesis ofthe Example 109.

TABLE 5

Example Reaction No. Name R Temperature 110 (4S)-2-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-7-(3,5- dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazine

23° C. 111 (4S)-2-[1- (cyclopropylcarbonyl)piperidin-4-yl]-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin- 2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine

23° C. 112 (4S)-7-(3,5-dimethylisoxazol-4-yl)-2-[1-(methylsulfonyl)piperidin-4-yl]-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazine

 0° C. 113A (4S)-2-(1-acetylpyrrolidin-3-yl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl- 4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine (diastereomer 1)

23° C. 113B (4S)-2-(1-acetylpyrrolidin-3-yl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl- 4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine (diastereomer 2)

23° C. 114A (4S)-2-[1- (cyclopropylcarbonyl)pyrrolidin-3-yl]-7-(3,5-dimethylisoxazol-4-yl)-4- pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine (diastereomer 1)

23° C. 114B (4S)-2-[1- (cyclopropylcarbonyl)pyrrolidin-3-yl]-7-(3,5-dimethylisoxazol-4-yl)-4- pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine (diastereomer 2)

23° C. 115 (4S)-7-(3,5-dimethylisoxazol-4-yl)-2-[1-(methylsulfonyl)pyrrolidin-3-yl]-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazine (mixture ofdiastereomers)

 0° C. 116 (4S)-2-(1-acetyl-1,2,5,6- tetrahydropyridin-3-yl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl- 4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine

23° C. 117 (4S)-2-(1-acetylpiperidin-3-yl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl- 4,5-dihydroimidazo[1,5,4-de[1,4]benzoxazine (mixture of diastereomers)

23° C. 118 (4S)-2-[1- (cyclopropylcarbonyl)piperidin-3-yl]-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin- 2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine (mixture of diastereomers)

23° C. 119 (4S)-7-(3,5-dimethylisoxazol-4-yl)-2-[1-(methylsulfonyl)piperidin-3-yl]-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazine (mixture ofdiastereomers)

 0° C.

Example 1207-(3,5-Dimethylisoxazol-4-yl)-4-phenyl-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one

Step 1. 2-Phenyl-1,2,3,4-tetrahydroquinoline

A solution of 2-phenylquinoline, (0.248 g, 1.21 mmol) [Aldrich, cat.#299650] in acetic acid (6.0 mL) was treated with borane-pyridinecomplex (0.605 mL, 5.99 mmol) and stirred at room temperature for 18 h.The reaction mixture was diluted with ethyl acetate (50 mL) and washedwith 3 M sodium hydroxide solution (70 mL), water (20 mL), and brine (20mL). The organic layer was dried over sodium sulfate, filtered, andconcentrated to give a crude oil. Purification by flash columnchromatography (100% hexanes to 25% ethyl acetate/hexanes) gave thedesired product (0.247 g, 98%) as a racemic mixture. LCMS calculated forC₁₅H₁₆N (M+H)⁺: m/z=210.1; found: 210.1.

Step 2. N-Methoxy-2-phenyl-3,4-dihydroquinoline-1 (2H)-carboxamide

A solution of 2-phenyl-1,2,3,4-tetrahydroquinoline (2.13 g, 10.2 mmol)and triethylamine (4.26 mL, 30.5 mmol) in tetrahydrofuran (30.0 mL) wasadded to a solution of triphosgene (3.20 g, 10.8 mmol) intetrahydrofuran (38.0 mL) at 0° C. The reaction mixture was stirred at0° C. for 1 h, treated with methoxylamine hydrochloride (1.70 g, 20.3mmol) and triethylamine (4.26 mL, 30.5 mmol), and stirred at roomtemperature for an additional 19 h. The reaction mixture was dilutedwith water (200 mL) and extracted with ethyl acetate (2×100 mL). Thecombined organic extracts were washed with brine, dried over sodiumsulfate, filtered, and concentrated to give a crude oil. Purification byflash column chromatography (100% hexanes to 70% ethyl acetate/hexanes,the ethyl acetate containing 5% methanol) gave the desired product (2.25g, 78%) as a racemic mixture. LCMS calculated for C₁₇H₁₉N₂O₂ (M+H)⁺:m/z=283.1; found: 283.1.

Step 3.1-Methoxy-4-phenyl-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one

A solution of N-methoxy-2-phenyl-3,4-dihydroquinoline-1(2H)-carboxamide(0.869 g, 3.08 mmol) in chloroform (23.2 mL) at 0° C. was with treatedwith [I,I-bis(trifluoroacetoxy)iodo]benzene (1.59 g, 3.69 mmol) in fourportions over 20 min. The resulting mixture was stirred at 0° C. for 30min and at room temperature for 30 min. The reaction mixture was thendiluted with saturated aqueous sodium bicarbonate solution (40 mL) andextracted with dichloromethane (50 mL). The organic layer was washedwith brine, dried over sodium sulfate, filtered, and concentrated togive a crude oil. Purification by flash column chromatography (100%hexanes to 70% ethyl acetate/hexanes, the ethyl acetate containing 5%methanol) gave the desired product (0.576 g, 66%) as a racemic mixture.LCMS calculated for C₁₇H₁₇N₂O₂ (M+H)⁺: m/z=281.1; found: 281.1.

Step 4. 4-Phenyl-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one

A suspension of1-methoxy-4-phenyl-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one(0.575 g, 2.05 mmol) in ethanol (35.9 mL, 615 mmol) was heated todissolve residual solids and the resulting solution was cooled to roomtemperature. The solution was treated with acetic acid (0.233 mL, 4.10mmol), degassed with nitrogen, treated with palladium catalyst (0.575 g,100 wt %) (10% Pd on carbon, Degussa type) and hydrogenated for 17 h.The reaction mixture was filtered and the catalyst was washed withethanol and methanol. The filtrate was then concentrated to give thedesired product (0.436 g, 85%) as a racemic mixture that was usedwithout further purification. LCMS calculated for C₁₆H₁₅N₂O (M+H)⁺:m/z=251.1; found: 251.1.

Step 5.7-Bromo-4-phenyl-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one

A suspension of4-phenyl-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (0.200 g,0.799 mmol) in acetonitrile (10.0 mL) and acetic acid (2.42 mL) washeated to dissolve residual solids and the resultant solution was cooledto 0° C. The resulting solution was treated with a solution ofN-bromosuccinimide (0.144 g, 0.807 mmol) in acetonitrile (3.0 mL), addeddropwise, at 0° C. and subsequently stirred at 0° C. for 1 h. Thereaction mixture was concentrated to a residue which was dissolved inchloroform (50 mL) and washed with saturated aqueous sodium bicarbonate(40 mL) and brine (20 mL). The organic layer was dried over sodiumsulfate, filtered, and concentrated to give a crude solid. Purificationby flash column chromatography (100% hexanes to 50% ethylacetate/hexanes, the ethyl acetate containing 5% methanol) gave thedesired product (0.177 g, 67%) as a racemic mixture along with anadditional other brominated isomer,8-bromo-4-phenyl-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one(which was not be separated) in a 4.4:1 ratio. LCMS calculated forC₁₆H₁₄BrN₂O (M+H)⁺: m/z=329.0, 331.0; found: 329.0, 331.0.

Step 6.7-(3,5-Dimethylisoxazol-4-yl)-4-phenyl-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one

A mixture of7-bromo-4-phenyl-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one(0.050 g, 0.15 mmol) (4.4:1 mixture of isomers with8-bromo-4-phenyl-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one asthe minor isomer), (3,5-dimethylisoxazol-4-yl)boronic acid (10.7 mg,0.0759 mmol), and cesium carbonate (99.0 mg, 0.304 mmol) in1,2-dimethoxyethane (1.21 mL) and water (0.303 mL) was degassed withnitrogen for 5 min. The reaction mixture was treated with PEPPSI-IPr(5.2 mg, 0.0076 mmol) [Aldrich, cat. #669032], degassed with nitrogenfor 5 min, and heated at 90° C. for 1 h. The reaction mixture was thendiluted with ethyl acetate (25 mL) and water (20 mL). The organic layerwas separated, washed with brine, dried over sodium sulfate, filtered,and concentrated to give a crude residue. Purification via preparativeLCMS (XBridge C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% trifluoroacetic acid, at flow rate of 60 mL/min) gavethe desired product (14.7 mg, 28%) as a racemic mixture. ¹H NMR (500MHz, CDCl₃) δ 10.00 (s, 1H), 7.34-7.20 (m, 3H), 7.08-6.95 (m, 3H),6.88-6.76 (m, 1H), 5.54 (s, 1H), 2.45-1.96 (m, 10H); LCMS calculated forC₂₁H₂₀N₃O₂ (M+H)⁺: m/z=346.2; found: 346.1.

Example 1217-(3,5-Dimethylisoxazol-4-yl)-1-methyl-4-phenyl-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one

A solution of7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one(10.7 g, 0.031 mmol) in N,N-dimethylformamide (0.50 mL) was treated withcesium carbonate (20.2 g, 0.062 mmol) followed by methyl iodide (2.9 μL,46.5 μmol) and stirred at room temperature for 16 h. Purification viapreparative LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% trifluoroacetic acid, at flow rate of60 mL/min) gave the desired product (8.2 mg, 74%) as a racemic mixture.¹H NMR (400 MHz, CDCl₃) δ 7.35-7.20 (m, 3H), 7.03 (d, J=6.9 Hz, 2H),6.99-6.93 (m, 1H), 6.93-6.84 (m, 1H), 5.53 (s, 1H), 3.49 (s, 3H),2.48-2.11 (m, 7H), 2.09-1.84 (m, 3H); LCMS calculated for C₂₂H₂₂N₃O₂(M+H)⁺: m/z=360.2; found: 360.1.

Example 1227-(3,5-Dimethylisoxazol-4-yl)-1-methoxy-4-pyridin-2-yl-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-onetrifluoroacetate

Step 1. 2-Pyridin-2-ylquinoline

A solution of 2-bromoquinoline (1.00 g, 4.81 mmol) [Aldrich, cat.#716278] in N,N-dimethylformamide (10.0 mL) (degassed with nitrogen) wastreated with 2-(tributylstannyl)pyridine (1.83 mL, 4.81 mmol) andbis(triphenylphosphine)palladium(II) chloride (0.337 g, 0.481 mmol). Thereaction mixture was degassed with nitrogen for 5 min and heated at 110°C. for 17 h. The reaction mixture was then diluted with water (50 mL)and ether (50 mL) and filtered over Celite. The solids were washed withadditional ether (150 mL). The filtrate was washed with water (150 mL)and brine, dried over sodium sulfate, filtered, and concentrated to givea crude residue. Purification by flash column chromatography (100%hexanes to 70% ethyl acetate/hexanes, the ethyl acetate containing 5%methanol) gave the desired product (0.771 g, 78%). LCMS calculated forC₁₄H₁₁N₂(M+H)⁺: m/z=207.1; found: 207.1.

Step 2. 2-Pyridin-2-yl-1,2,3,4-tetrahydroquinoline

A suspension of 2-pyridin-2-ylquinoline (0.767 g, 3.72 mmol),1,4-dihydro-3,5-dicarbethoxy-2,6-dimethylpyridine (2.17 g, 8.55 mmol),and diphenyl hydrogen phosphate (0.0093 g, 0.037 mmol) in benzene (18.6mL) was heated at 60° C. for 10 h. The reaction mixture was treated with2-phenylquinoline (0.305 g, 1.49 mmol) and heated at 60° C. for 3 h. Thereaction mixture was then concentrated to a crude solid. Purification byflash column chromatography (100% hexanes to 50% ethyl acetate/hexanes[the ethyl acetate contained 5% methanol]) gave the desired product (0.735 g, 94%) as a racemic mixture. LCMS calculated for C₁₄H₁₅N₂(M+H)⁺:m/z=211.1; found: 211.1.

Step 3. N-Methoxy-2-pyridin-2-yl-3,4-dihydroquinoline-1(2H)-carboxamide

A solution of 2-pyridin-2-yl-1,2,3,4-tetrahydroquinoline (0.723 g, 3.44mmol) in methylene chloride (10.3 mL) was treated with 4-nitrophenylmethoxycarbamate (0.948 g, 4.47 mmol) (Org. Process Res. Dev. 2012, 16,109-116) followed by the dropwise addition of N, N-diisopropylethylamine(1.20 mL, 6.88 mmol), and the resulting mixture was stirred at roomtemperature for 1.5 h. The reaction mixture was then poured over water(25 mL) and saturated sodium bicarbonate (25 mL) and extracted withdichloromethane (2×50 mL). The combined organic layers were dried oversodium sulfate, filtered, and concentrated to give a crude oily solid.Purification by flash column chromatography (100% hexanes to 20% ethylacetate/hexanes [the ethyl acetate contained 5% methanol]) gave thedesired product (0.923 g, 95%) as a racemic mixture. LCMS calculated forC₁₆H₁₈N₃O₂ (M+H)⁺: m/z=284.1; found: 284.0.

Step 4.1-Methoxy-4-pyridin-2-yl-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one

This compound was synthesized according to the procedure of Example 120,step 3, usingN-methoxy-2-pyridin-2-yl-3,4-dihydroquinoline-1(2H)-carboxamide as thestarting material. LCMS calculated for C₁₆H₁₆N₃O₂ (M+H)⁺: m/z=282.1;found: 282.0.

Step 5.7-Bromo-1-methoxy-4-pyridin-2-yl-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one

This compound was synthesized according to the procedure of Example 120,step 5, using1-methoxy-4-pyridin-2-yl-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-oneas the starting material. LCMS calculated for C₁₆H₁₅BrN₃O₂(M+H)⁺:m/z=360.0, 362.0; found: 359.9, 361.9.

Step 6.7-(3,5-Dimethylisoxazol-4-yl)-1-methoxy-4-pyridin-2-yl-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-onetrifluoroacetate

A suspension of7-bromo-1-methoxy-4-pyridin-2-yl-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one(0.132 g, 0.367 mmol) (as a mixture of brominated isomers), and cesiumfluoride (0.195 g, 1.29 mmol) in tert-butyl alcohol (1.22 mL) and water(0.612 mL) degassed with nitrogen for 10 min. The reaction mixture wastreated with (3,5-dimethylisoxazol-4-yl)boronic acid (0.0518 g, 0.367mmol) followed by addition of4-(di-tert-butylphosphino)-N,N-dimethylaniline-dichloropalladium (2:1)(5.2 mg, 7.35 μmol). The mixture was degassed with nitrogen for anadditional 5 min, and heated at 80° C. for 1.5 h, at which time thereaction mixture was treated with cesium fluoride (0.0558 g, 0.367mmol), (3,5-dimethylisoxazol-4-yl)boronic acid (0.104 g, 0.735 mmol),and 4-(di-tert-butylphosphino)-N,N-dimethylaniline-dichloropalladium(2:1) (5.20 mg, 0.00735 mmol), degassed with nitrogen, and stirred at100° C. for 14 h. The reaction mixture was diluted with ethyl acetate(40 mL) and water (20 mL). The organic layer was separated, washed withbrine, dried over sodium sulfate, filtered, and concentrated to give acrude residue. Purification by flash column chromatography (100% hexanesto 20% ethyl acetate/hexanes, the ethyl acetate containing 5% methanol)yielded a crude product. Further purification via preparative LCMS(XBridge C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% trifluoroacetic acid, at flow rate of 60 mL/min) gavethe desired product (95 mg, 53%) as a racemic mixture. ¹H NMR (500 MHz,DMSO-d₆) δ 8.52 (d, J=4.3 Hz, 1H), 7.84 (dd, J=7.5 Hz, 1H), 7.42-7.31(m, 1H), 7.31-7.23 (m, 1H), 7.18 (d, J=7.9 Hz, 1H), 7.04-6.90 (m, 1H),5.44 (s, 1H), 4.02 (s, 3H), 2.54-2.46 (m, 3H), 2.45-2.31 (m, 2H),2.29-2.16 (m, 2H), 2.08 (d, J=25.9 Hz, 3H); LCMS calculated forC₂₁H₂₁N₄O₃ (M+H)⁺: m/z=377.2; found: 377.0.

Example 1237-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-onetrifluoroacetate

Step 1.4-Pyridin-2-yl-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one

This compound was synthesized according to the procedure of Example 120,step 4, using1-methoxy-4-pyridin-2-yl-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-oneas the starting material. LCMS calculated for C₁₅H₁₄N₃O (M+H)⁺:m/z=252.1; found: 252.1.

Step 2.7-Bromo-4-pyridin-2-yl-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one

This compound was synthesized according to the procedure of example 120,step 5, using4-pyridin-2-yl-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one as thestarting material. LCMS calculated for C₁₅H₁₃BrN₃O (M+H)⁺: m/z=330.0,332.0; found: 329.9, 331.9.

Step 3.7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-onetrifluoroacetate

This compound was synthesized according to the procedure of Example 120,step 6, using7-bromo-4-pyridin-2-yl-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-oneas the starting material. ¹H NMR (500 MHz, DMSO-d₆) δ 10.89 (s, 1H),8.55 (d, J=4.3 Hz, 1H), 7.85 (dd, J=7.3 Hz, 1H), 7.49-7.31 (m, 1H),7.25-7.10 (m, 1H), 6.96 (d, J=7.9 Hz, 1H), 6.90-6.72 (m, 1H), 5.41 (s,1H), 2.55-2.28 (m, 5H), 2.27-1.89 (m, 5H); LCMS calculated forC₂₀H₁₉N₄O₂ (M+H)⁺: m/z=347.1; found: 347.1.

Example 1247-[5-(Hydroxymethyl)-3-methylisoxazol-4-yl]-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one

Step 1. Prop-2-yn-1-yl benzoate

A solution of 2-propyn-1-ol (10.0 mL, 172 mmol) in methylene chloride(496 mL) and triethylamine (47.9 mL, 344 mmol) at 0° C. was treated withbenzoyl chloride (20.0 mL, 172 mmol), added over a period of 5 min. Thereaction mixture was stirred at 0° C. for 30 min, followed by additionalstirring at room temperature for 2 h. The reaction mixture was quenchedwith water (300 mL). The aqueous layer was separated and extracted withdichloromethane (2×200 mL). The combined organic layers were washed withwater (2×200 mL) and brine (100 mL), dried over magnesium sulfate,filtered, and concentrated to give the desired product (27 g, 98%) whichwas used without further purification. LCMS calculated for C₁₀H₉O₂(M+H)⁺: m/z=161.1; found: 161.0.

Step 2. (3-Methylisoxazol-5-yl)methyl benzoate

A solution of prop-2-yn-1-yl benzoate (26.0 g, 162 mmol) in chloroform(598 mL) was treated with triethylamine (11.3 mL, 81.2 mmol) andacetaldoxime (14.4 g, 244 mmol). The reaction mixture was cooled to 0°C., treated with sodium hypochlorite (551 mL, 487 mmol) (commercialgrade ˜5% aqueous), and stirred overnight at room temperature. Thelayers were separated and the aqueous layer was extracted withdichloromethane (2×200 mL). The combined organic layers were washed withwater and brine, dried over magnesium sulfate, filtered, andconcentrated to give the crude product. Purification by flash columnchromatography (100% hexanes to 30% ethyl acetate/hexanes) gave thedesired product (20.1 g, 57%). LCMS calculated for C₁₂H₁₂NO₃ (M+H)⁺:m/z=218.1; found: 218.1.

Step 3. (4-Bromo-3-methylisoxazol-5-yl)methyl benzoate

A solution of (3-methylisoxazol-5-yl)methyl benzoate (20.1 g, 92.4 mmol)in acetic acid (77.3 mL) was treated with N-bromosuccinimide (19.7 g,111 mmol) and heated in a sealed tube at 90° C. for 4 h. The reactionmixture was diluted with brine and extracted with ethyl acetate. Theorganic layer was separated, washed with brine, dried over magnesiumsulfate, filtered, and concentrated to give the crude product.Purification by flash column chromatography (100% hexanes to 20% ethylacetate/hexanes) gave the desired product (21.6 g, 79%). LCMS calculatedfor C₁₂H₁₁BrNO₃ (M+H)⁺: m/z=296.0, 298.0; found: 296.0, 298.0.

Step 4. {5-[(Benzoyloxy)methyl]-3-methylisoxazol-4-yl}boronic acid

A flask containing bis(acetonitrile)palladium(II) chloride (0.40 g, 1.6mmol) and 2′-(dicyclohexylphosphino)-N,N-dimethylbiphenyl-2-amine (2.10g, 5.34 mmol) was evacuated and back-filled with nitrogen (repeated forthree cycles). Addition of (4-bromo-3-methylisoxazol-5-yl)methylbenzoate (14.9 g, 50.4 mmol) (as a solution in 1,4-dioxane (32 mL)), wasfollowed by addition of 1.0 M 4,4,5,5-tetramethyl-1,3,2-dioxaborolane intetrahydrofuran (85.7 mL), and triethylamine (21.1 mL, 151 mmol). Theresulting mixture was bubbled with nitrogen for 5 min and then heated at100° C. for 1 h. The reaction mixture was then diluted with ethylacetate and water. The organic layer was separated, washed with brine,dried over magnesium sulfate, filtered, and concentrated to give crudeboronate ester. Purification by flash column chromatography (100%hexanes to 40% ethyl acetate/hexanes) gave the intermediate boronateester. The purified boronate ester was dissolved in tetrahydrofuran (110mL), diluted with water (50 mL), and treated with sodium periodate (20.3g, 94.7 mmol). The reaction mixture was stirred vigorously for 15 min,treated with 1.0 M hydrogen chloride in water (64.0 mL), and stirred atroom temperature for 2 h. The reaction mixture was then extracted withethyl acetate (3×60 mL), washed with water and brine, dried overmagnesium sulfate, filtered, and concentrated to give the crude boronicacid. Recrystallization from ethyl acetate/hexanes gave the desiredproduct (2.2 g). The filtrate was concentrated and the resulting residuewas washed with hexanes to yield additional product (4.85 g) (7.05 gtotal, 54% combined yield). LCMS calculated for C₁₂H₁₃BNO₅ (M+H)⁺:m/z=262.1; found: 262.1.

Step 5.[3-Methyl-4-(2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-7-yl)isoxazol-5-yl]methyl benzoate

A solution of7-bromo-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one(687 mg, 2.07 mmol) and{5-[(benzoyloxy)methyl]-3-methylisoxazol-4-yl}boronic acid (1.08 g, 4.14mmol) in 1,4-dioxane (15.7 mL) and water (4 mL) was degassed withnitrogen. The reaction mixture was treated with[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (1:1) (253 mg, 0.310 mmol), degassed with nitrogen,and heated in a sealed tube at 80° C. for 30 min, at which time thereaction mixture was treated with{5-[(benzoyloxy)methyl]-3-methylisoxazol-4-yl}boronic acid (1.08 g, 4.14mmol) and [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II),complex with dichloromethane (1:1) (10 mg, 12.2 μmol), degassed withnitrogen and heated at 80° C. for a further 30 min. The reaction mixturewas then diluted with ethyl acetate and water. The organic layer wasseparated and washed with brine, dried over magnesium sulfate, filtered,and concentrated to give the crude product. Purification by flash columnchromatography (30% ethyl acetate/hexanes to 100% ethyl acetate [theethyl acetate contained 5% methanol]) gave the desired product (0.589 g,58%) as a racemic mixture. LCMS calculated for C₂₆H₂₁N₄O₅ (M+H)⁺:m/z=469.1; found: 469.1.

Step 6.7-[5-(Hydroxymethyl)-3-methylisoxazol-4-yl]-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one

A solution of[3-methyl-4-(2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-7-yl)isoxazol-5-yl]methylbenzoate (15.0 mg, 0.0320 mmol) in tetrahydrofuran (1.0 mL) and methanol(1.0 mL) was treated with 2.0 M lithium hydroxide in water (0.10 mL,0.20 mmol) and stirred at room temperature for 20 min. The reactionmixture was quenched with 6 N hydrogen chloride in water (to pH ˜2) andthen concentrated. Purification by preparative LCMS (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% ammoniumhydroxide, at flow rate of 30 mL/min) gave the desired product (8 mg,69%) as a racemic mixture. ¹H NMR (300 MHz, DMSO-d₆) δ 8.51 (d, J=4.8Hz, 1H), 7.77 (ddd, J=7.7, 7.7, 1.7 Hz, 1H), 7.31 (dd, J=7.4, 4.9 Hz,1H), 7.09 (d, J=7.9 Hz, 1H), 6.85 (d, J=8.0 Hz, 1H), 6.75 (d, J=8.0 Hz,1H), 5.51 (s, 1H), 4.77 (dd, J=11.4, 1.8 Hz, 1H), 4.42 (dd, J=11.4, 3.1Hz, 1H), 4.36 (s, 2H), 3.15 (s, 1H), 2.06 (s, 3H); LCMS calculated forC₁₉H₁₇N₄O₄ (M+H)⁺: m/z=365.1; found: 365.1.

Example 1257-[5-(Fluoromethyl)-3-methylisoxazol-4-yl]-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-onetrifluoroacetate

A solution of7-[5-(hydroxymethyl)-3-methylisoxazol-4-yl]-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one(15.0 mg, 0.0412 mmol) in methylene chloride (0.30 mL) was cooled to−78° C., treated with dimethylaminosulfur trifluoride (6.03 mg, 0.0453mmol) and was allowed to warm to room temperature overnight. Thereaction mixture was then concentrated to give a crude residue.Purification via preparative LCMS (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% trifluoroacetic acid, atflow rate of 30 mL/min) gave the desired product (8 mg, 40%) as aracemic mixture. ¹H NMR (300 MHz, CD₃OD) δ 8.59 (d, J=4.2 Hz, 1H), 7.89(ddd, J=7.8, 7.8, 1.7 Hz, 1H), 7.43 (dd, J=7.5, 5.0 Hz, 1H), 7.20 (d,J=7.9 Hz, 1H), 6.97 (d, J=8.1 Hz, 1H), 6.90 (d, J=8.1 Hz, 1H), 5.60 (dd,J=2.7, 2.7 Hz, 1H), 5.37 (s, 1H), 5.21 (s, 1H), 4.82 (dd, J=11.5, 2.6Hz, 1H), 4.52 (dd, J=11.5, 3.2 Hz, 1H), 2.19 (s, 3H); LCMS calculatedfor C₁₉H₁₆FN₄O₃(M+H)⁺: m/z=367.1; found: 367.1.

Example 1263-[7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]pyridine-2-carbonitrile

Step 1. 2-Bromo-1-(2-bromopyridin-3-yl)ethanone

A solution of 1-(2-bromopyridin-3-yl)ethanone (2.10 g, 10.5 mmol) inacetic acid (28.0 mL) was treated with bromine (595 μL, 11.5 mmol) andheated at 90° C. for 1 h. The reaction mixture was diluted with ethylacetate and saturated aqueous sodium bicarbonate solution. The aqueouslayer was separated and further extracted with ethyl acetate (2×80 mL).The combined organic layers were washed with brine, dried over magnesiumsulfate, filtered, and concentrated to give the crude product.Purification by flash column chromatography (10% ethyl acetate/hexanesto 30% ethyl acetate/hexanes) gave the desired product (2.15 g, 73%).LCMS calculated for C₇H₆Br₂NO (M+H)⁺: m/z=277.9, 279.9, 281.9; found:277.7, 279.7, 281.8.

Step 2.3-(2-Bromopyridin-3-yl)-5-nitro-3,4-dihydro-2H-1,4-benzoxazin-3-ol

A solution of 2-bromo-1-(2-bromopyridin-3-yl)ethanone (2.15 g, 7.71mmol) in methylene chloride (77.1 mL) and water (19.3 mL) was treatedwith potassium carbonate (2.13 g, 15.4 mmol), tetra-N-butylammoniumbromide (500 mg, 1.50 mmol), and 2-amino-3-nitrophenol (1.31 g, 8.48mmol), and heated at 40° C. for 5 h. The reaction mixture was thendiluted with brine. The aqueous layer was separated and extracted withdichloromethane (2×100 mL). The combined organic layers were washed withwater and brine, dried over magnesium sulfate, filtered, andconcentrated to give the crude product. Purification by flash columnchromatography (100% hexanes to 35% ethyl acetate/hexanes) gave thedesired product (2.45 g, 90%) as a racemic mixture. LCMS calculated forC₁₃H₁₁BrN₃O₄(M+H)⁺: m/z=352.0, 354.0; found: 351.7, 353.8.

Step 3. 3-(2-Bromopyridin-3-yl)-2H-1,4-benzoxazin-5-amine

A suspension of iron (1.71 g, 30.7 mmol) (<10 micron) in ethanol (33.5mL) was treated with 1.0 M hydrogen chloride in water (3.1 mL, 3.1 mmol)and was stirred at 60° C. for 2 h. The mixture was then cooled to 55-60°C. and treated with 5.0 M ammonium chloride in water (5.3 mL, 26.4 mmol)followed by addition of3-(2-bromopyridin-3-yl)-5-nitro-3,4-dihydro-2H-1,4-benzoxazin-3-ol (2.16g, 6.13 mmol, washed with 5 mL ethanol). The resulting suspension wasstirred at 60-65° C. for 2 h. The suspension was diluted withacetonitrile to about 100 mL and filtered over Celite. The solid waswashed with additional acetonitrile and the filtrate was concentrated toa solid. This solid was dissolved in ethyl acetate which was then driedover magnesium sulfate, filtered, and concentrated to give the desiredproduct (1.85 g, 99%), used without further purification. LCMScalculated for C₁₃H₁₁BrN₃O (M+H)⁺: m/z=304.0, 306.0; found: 304.0,306.0.

Step 4. 3-(2-Bromopyridin-3-yl)-3,4-dihydro-2H-1,4-benzoxazin-5-aminetris-trifluoroacetate

A suspension of 3-(2-bromopyridin-3-yl)-2H-1,4-benzoxazin-5-amine (1.85g, 6.08 mmol) in ethanol (20.0 mL) and water (4.0 mL) was treated withsodium tetrahydroborate (460 mg, 12.2 mmol) and stirred at roomtemperature overnight, at which time the mixture was treated withadditional sodium tetrahydroborate (200 mg, 5.3 mmol) and heated at 90°C. for 2 h. The reaction mixture was quenched with acetic acid anddiluted with ethyl acetate. The organic layer was separated and washedwith saturated aqueous sodium bicarbonate, water and brine, dried overmagnesium sulfate, filtered, and concentrated to give the crude product.Purification via preparative LCMS (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% trifluoroacetic acid, atflow rate of 60 mL/min) gave the desired product (1.69 g, 66%) as aracemic mixture. LCMS calculated for C₁₃H₁₃BrN₃O (M+H)⁺: m/z=306.0,308.0; found: 305.9, 307.9.

Step 5.4-(2-Bromopyridin-3-yl)-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one

A solution of3-(2-bromopyridin-3-yl)-3,4-dihydro-2H-1,4-benzoxazin-5-aminetris-trifluoroacetate (1.69 g, 4.01 mmol) in ethyl acetate (17.8 mL) at50° C. was treated with N,N-carbonyldiimidazole (0.78 g, 4.8 mmol) andstirred at 50° C. for 1 h. The reaction mixture was then cooled to 0° C.The resulting precipitate was collected via filtration and washed withether. The filtrate was concentrated to give a crude solid. Purificationby preparative LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of30 mL/min) gave the desired product that was combined with theprecipitated material (0.970 g total, 73% combined yield) as a racemicmixture. LCMS calculated for C₁₄H₁₁BrN₃O₂(M+H)⁺: m/z=332.0, 334.0;found: 331.8, 333.8.

Step 6.3-(2-Oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl)pyridine-2-carbonitrile

A suspension of4-(2-bromopyridin-3-yl)-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one(964 mg, 2.90 mmol), zinc cyanide (1.00 g, 8.70 mmol) andtetrakis(triphenylphosphine)palladium(0) (335 mg, 0.290 mmol) inN,N-dimethylformamide (20.4 mL) was degassed and heated in a microwaveat 160° C. for 20 min. The reaction mixture was diluted with ethylacetate and washed with saturated aqueous sodium bicarbonate, water andbrine, dried over magnesium sulfate, filtered, and concentrated to givethe crude product. The crude product was suspended in hot ethyl acetateand diluted with hexanes to twice the volume, which resulted in theprecipitation of a solid. The solid was collected by filtration andwashed with ethyl acetate to give the desired product (656 mg). Thefiltrate was concentrated to a residue which was purified by preparativeLCMS (XBridge C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to givethe desired product that was combined with the precipitated material(0.709 g total, 88% combined yield) as a racemic mixture. LCMScalculated for C₁₅H₁₁N₄O₂ (M+H)⁺: m/z=279.1; found: 278.9.

Step 7.3-(7-Bromo-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl)pyridine-2-carbonitrile

A solution of3-(2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl)pyridine-2-carbonitrile(709 mg, 2.548 mmol) in N,N-dimethylformamide (25.0 mL) was treated withN-bromosuccinimide (630 mg, 3.54 mmol) and stirred at room temperatureovernight. The reaction mixture was diluted with ethyl acetate andwashed with water and brine, dried over magnesium sulfate, filtered, andconcentrated to give the crude product. Purification by preparative LCMS(XBridge C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% ammonium hydroxide, at flow rate of 60 mL/min) gave thedesired product (0.44 g, 48%) as a racemic mixture. LCMS calculated forC₁₅H₁₀BrN₄O₂(M+H)⁺: m/z=357.0, 359.0; found: 356.8, 358.8.

Step 8.3-[7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]pyridine-2-carbonitrile

A sealed tube containing4-(di-tert-butylphosphino)-N,N-dimethylaniline-dichloropalladium (2:1)(11.5 mg, 0.0162 mmol), cesium fluoride (574 mg, 3.78 mmol),3-(7-bromo-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl)pyridine-2-carbonitrile(386 mg, 1.01 mmol) and (3,5-dimethylisoxazol-4-yl)boronic acid (533 mg,3.78 mmol) was placed under vacuum and back-filled with nitrogen(repeated 3×). The sealed tube was charged with 1-butanol (4.92 mL) andwater (1.2 mL) and the mixture was degassed by bubbling nitrogen for 15min and heated at 100° C. for 2 h. The reaction mixture was diluted withethyl acetate, washed with water and brine, dried over magnesiumsulfate, filtered, and concentrated to give the crude product.Purification by preparative LCMS (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% ammonium hydroxide, atflow rate of 60 mL/min) gave the desired product (342 mg, 85%) as aracemic mixture. ¹H NMR (300 MHz, DMSO-d₆) δ 11.00 (br s, 1H), 8.81-8.66(m, 1H), 7.80-7.62 (m, 2H), 6.90 (d, J=8.0 Hz, 1H), 6.80 (d, J=8.0 Hz,1H), 5.74-5.51 (m, 1H), 4.58 (d, J=3.4 Hz, 2H), 2.29 (s, 3H), 2.12 (s,3H); LCMS calculated for C₂₀H₁₆N₅O₃ (M+H)⁺: m/z=374.1; found: 374.1.

Example 1273-[7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]pyridine-2-carboxamidetrifluoroacetate

A solution of3-[7-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]pyridine-2-carbonitrile(12.0 mg, 0.0321 mmol) in dimethyl sulfoxide (120 μL) at 0° C. wastreated with hydrogen peroxide (5.36 μL, 0.0524 mmol) (30% solution),followed by potassium carbonate (1 mg, 0.008 mmol) and stirred overnightat room temperature. Purification via preparative LCMS (XBridge C18column, eluting with a gradient of acetonitrile/water containing 0.1%trifluoroacetic acid, at flow rate of 30 mL/min) gave the desiredproduct (10 mg, 62%) as a racemic mixture. ¹H NMR (300 MHz, DMSO-d₆) δ11.06 (s, 1H), 8.73-8.49 (m, 1H), 8.34 (s, 1H), 7.84 (s, 1H), 7.49 (dd,J=8.0, 4.6 Hz, 1H), 7.11 (d, J=7.9 Hz, 1H), 6.88 (d, J=8.0 Hz, 1H), 6.81(d, J=8.0 Hz, 1H), 6.56-6.41 (m, 1H), 4.53 (d, J=2.1 Hz, 2H), 2.24 (s,3H), 2.07 (s, 3H); LCMS calculated for C₂₀H₁₈N₅O₄ (M+H)⁺: m/z=392.1;found: 392.1.

Example 1283-[7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]-N-methylpyridine-2-carboxamide

Step 1.3-[7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]pyridine-2-carboxylicacid hydrochloride

A solution of3-[7-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]pyridine-2-carbonitrile(342 mg, 0.916 mmol) in 6.0 M hydrogen chloride in water (32.6 mL, 196mmol) was heated in the microwave at 160° C. for 30 min. The reactionmixture was concentrated to give the desired product (357 mg, 91%) as aracemic mixture which was used without further purification. LCMScalculated for C₂₀H₁₇N₄O₅ (M+H)⁺: m/z=393.1; found: 392.9.

Step 2.3-[7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]-N-methylpyridine-2-carboxamide

A solution of3-[7-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]pyridine-2-carboxylicacid (10.0 mg, 0.026 mmol) in N,N-dimethylformamide (0.50 mL) wastreated with methylammonium chloride (4.30 mg, 0.064 mmol) followed byN,N-diisopropylethylamine (22.2 μL, 0.127 mmol) and stirred at roomtemperature for 5 min. The reaction mixture was treated withbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate[Aldrich #: 226084] (16.9 mg, 0.038 mmol) and stirred at roomtemperature for 1 h. Purification by preparative LCMS (XBridge C18column, eluting with a gradient of acetonitrile/water containing 0.1%ammonium hydroxide, at flow rate of 60 mL/min) gave the desired product(5 mg, 48%) as a racemic mixture. ¹H NMR (300 MHz, DMSO-d₆) δ 9.06-8.91(m, 1H), 8.57 (d, J=3.6 Hz, 1H), 7.49 (dd, J=8.1, 4.6 Hz, 1H), 7.10 (d,J=7.4 Hz, 1H), 6.93-6.74 (m, 2H), 6.47 (s, 1H), 4.65-4.37 (m, 2H), 2.62(d, J=10.1 Hz, 6H), 2.24 (s, 1.5H), 2.07 (s, 1.5H); LCMS calculated forC₂₁H₂₀N₅O₄ (M+H)⁺: m/z=406.1; found: 406.1.

Example 1293-[7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]-N,N-dimethylpyridine-2-carboxamide

The title compound was synthesized according to the procedure of Example128, step 2, substituting dimethylamine as the starting material. ¹H NMR(300 MHz, DMSO-d₆) δ 8.53 (dd, J=4.6, 1.5 Hz, 1H), 7.40 (dd, J=8.0, 4.7Hz, 1H), 7.33 (dd, J=8.0, 1.5 Hz, 1H), 6.86 (d, J=8.0 Hz, 1H), 6.78 (d,J=8.0 Hz, 1H), 5.27 (dd, J=3.3, 3.3 Hz, 1H), 4.47-4.28 (m, 2H), 3.04 (s,1.5H), 2.86 (s, 1.5H), 2.62 (d, J=10.1 Hz, 6H), 2.27 (s, 1.5H), 2.10 (s,1.5H); LCMS calculated for C₂₂H₂₂N₅O₄ (M+H)⁺: m/z=420.2; found: 420.1.

Example 1304-[2-(Aminomethyl)pyridin-3-yl]-7-(3,5-dimethylisoxazol-4-yl)-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-onebis(trifluoroacetate)

A solution of3-[7-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]pyridine-2-carbonitrile(50.0 mg, 0.134 mmol) in methanol (25.0 mL) and 6.0 M hydrogen chloridein water (0.250 mL, 1.50 mmol) in a Parr bottle was flushed withnitrogen and treated with palladium catalyst (28.5 mg, 0.013 mmol) (10%Pd on carbon, Degussa type). The reaction vessel was charged to 50 PSIhydrogen and shaken for 5 h. The reaction mixture was then filtered overCelite. The solids were washed with additional methanol (150 mL) and thefiltrate was concentrated to give the crude product. Purification viapreparative LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% trifluoroacetic acid, at flow rate of60 mL/min) gave the desired product (39 mg, 48%) as a racemic mixture.¹H NMR (300 MHz, DMSO-d₆) δ 11.08 (s, 1H), 8.60 (dd, J=4.5, 1.8 Hz, 1H),8.48-8.23 (m, 2H), 7.54-7.28 (m, 2H), 6.90 (d, J=8.0 Hz, 1H), 6.80 (d,J=8.0 Hz, 1H), 5.80-5.54 (m, 1H), 4.85-4.30 (m, 4H), 2.29 (s, 3H), 2.12(s, 3H); LCMS calculated for C₂₀H₂₀N₅O₃ (M+H)⁺: m/z=378.2; found: 378.1.

Example 131N-({3-[7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]pyridin-2-yl}methyl)acetamide

A solution of4-[2-(aminomethyl)pyridin-3-yl]-7-(3,5-dimethylisoxazol-4-yl)-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-onebis(trifluoroacetate) (35.0 mg, 0.058 mmol) in methylene chloride (2.0mL) was treated with N,N-diisopropylethylamine (50.3 μL, 0.289 mmol) andstirred. Once the starting material was completely dissolved, thereaction mixture was treated with acetyl chloride (49.3 μL, 0.069 mmol)(added as a 10% solution in dichloromethane) and stirred at roomtemperature for 1 h. The reaction mixture was quenched with methanol andthe solvent was concentrated to give the crude product. Purification bypreparative LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of60 mL/min) gave the desired product (18 mg, 74%) as a racemic mixture.¹H NMR (500 MHz, DMSO-d₆) δ 10.98 (br s, 1H), 8.50-8.47 (m, 1H), 8.44(dd, J=5.2, 5.2 Hz, 1H), 7.26 (dd, J=7.9, 4.7 Hz, 1H), 7.23-7.16 (m,1H), 6.88 (d, J=8.0 Hz, 1H), 6.78 (d, J=8.0 Hz, 1H), 5.68 (dd, J=3.1,3.1 Hz, 1H), 4.71 (dd, J=15.1, 6.1 Hz, 1H), 4.55-4.47 (m, 2H), 4.44 (dd,J=11.6, 3.2 Hz, 1H), 2.28 (s, 3H), 2.12 (s, 3H), 1.88 (s, 3H); LCMScalculated for C₂₂H₂₂N₅O₄ (M+H)⁺: m/z=420.2; found: 420.1.

Example 132 Methyl3-[7-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]pyridine-2-carboxylate

A solution of3-[7-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]pyridine-2-carboxylicacid (294 mg, 0.7493 mmol) in methanol (60.0 mL) was treated with onedrop of concentrated sulfuric acid and heated in a sealed tube overnightat 80° C. The reaction mixture was then concentrated to a crude residue.This residue was diluted with ethyl acetate (100 mL) and saturatedaqueous sodium bicarbonate solution and stirred at room temperature for1 hour. After dissolution, the aqueous layer was separated and extractedwith ethyl acetate (2×). The combined organic layers were washed withwater and brine, dried over magnesium sulfate, filtered, andconcentrated to give the crude product. Purification by preparative LCMS(XBridge C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% ammonium hydroxide, at flow rate of 60 mL/min) gave thedesired product (300 mg, 99%) as a racemic mixture. ¹H NMR (400 MHz,DMSO-d₆) δ 8.63 (dd, J=4.6, 1.5 Hz, 1H), 7.56 (dd, J=8.1, 4.6 Hz, 1H),7.29 (dd, J=8.1, 1.4 Hz, 1H), 6.89 (d, J=8.0 Hz, 1H), 6.80 (d, J=8.0 Hz,1H), 6.00 (dd, J=2.9, 2.9 Hz, 1H), 4.53 (d, J=2.9 Hz, 2H), 3.91 (s, 3H),2.26 (s, 3H), 2.09 (s, 3H); LCMS calculated for C₂₁H₁₉N₄O₅ (M+H)⁺:m/z=407.1; found: 407.0.

Example 133 Single enantiomer of3-[7-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]-N-ethylpyridine-2-carboxamide

Step 1. Separation of isomers of3-[7-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]pyridine-2-carbonitrile

The racemic mixture of3-[7-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]pyridine-2-carbonitrilewas separated by chiral HPLC (Phenomenex Lux Cellulose C2 column,21.2×250 mm, 5 micron particle size, eluting with 60% ethanol in hexanesat 18 mL/min, 90 mg per injection) to give peak 1 (RT=9.2 min) and peak2 (RT=15.9 min). Peak 1 was determined to be more active and was usedfor the synthesis of subsequent analogs.

Step 2. Single enantiomer of3-[7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]pyridine-2-carboxylicacid

A solution of3-[7-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]pyridine-2-carbonitrile(2.23 g, 5.97 mmol) (Peak 1 from step 1) in 6.0 M hydrogen chloride inwater (50 mL, 300 mmol) was heated in the microwave at 160° C. for 30min. The reaction mixture was concentrated to give the crude product.Purification by preparative LCMS (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% ammonium hydroxide, atflow rate of 60 mL/min) gave the desired product (1.41 g, 60%) as asingle enantiomer. LCMS calculated for C₂₀H₁₇N₄O₅ (M+H)⁺: m/z=393.1;found: 393.1.

Step 3.3-[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]-N-ethylpyridine-2-carboxamide

A solution of3-[7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]pyridine-2-carboxylicacid (30.0 mg, 0.0764 mmol) (from step 2) in N, N-dimethylformamide (1.0mL) was treated with ethylamine (10.8 μL, 0.191 mmol) followed byN,N-diisopropylethylamine (66.6 μL, 0.382 mmol) and stirred at roomtemperature for 5 min. The reaction mixture was subsequently treatedwith benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate [Aldrich #: 226084] (50.7 mg, 0.115 mmol) andstirred at room temperature for 1 h. Purification by preparative LCMS(XBridge C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% ammonium hydroxide, at flow rate of 60 mL/min) gave thedesired product (23 mg, 71%) as a single enantiomer. ¹H NMR (400 MHz,DMSO-d₆) δ 9.03 (t, J=5.9 Hz, 1H), 8.58 (dd, J=4.6, 1.4 Hz, 1H), 7.49(dd, J=8.0, 4.6 Hz, 1H), 7.11 (dd, J=8.0, 1.2 Hz, 1H), 6.87 (d, J=8.0Hz, 1H), 6.80 (d, J=8.0 Hz, 1H), 6.54-6.41 (m, 1H), 4.64-4.45 (m, 2H),3.43-3.24 (m, 2H), 2.24 (s, 3H), 2.07 (s, 3H), 1.15 (t, J=7.2 Hz, 3H);LCMS calculated for C₂₂H₂₂N₅O₄ (M+H)⁺: m/z=420.2; found: 420.2.

Examples 134-136

Examples 134-136 listed in Table 6 were synthesized as singleenantiomers according to the procedure of Example 133.

TABLE 6

Ex. No. Name R 134 N-Cyclopropyl-3-[7-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2,4,5- tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]pyridine-2- carboxamide

135 3-[7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4- de][1,4]benzoxazin-4-yl]-N-(2-hydroxyethyl)pyridine-2-carboxamide

136 3-[7-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4- de][1,4]benzoxazin-4-yl]-N-(2,2,2-trifluoroethyl)pyridine-2-carboxamide

Example 137(4S)-9-(Aminomethyl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-onebis(trifluoroacetate)

Step 1.(4S)-9-Bromo-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one

A solution of(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one(2.50 g, 7.18 mmol) in tetrahydrofuran (47 mL) was treated withN-bromosuccinimide (1.40 g, 7.89 mmol) and stirred at room temperaturefor 1 h, at which time the reaction mixture was treated with additionalN-bromosuccinimide (0.70 g, 3.93 mmol) and stirred at 45° C. for 3 h.The reaction mixture was diluted with ethyl acetate and washed withwater and brine, dried over magnesium sulfate, filtered, andconcentrated to give the crude product. Purification by flash columnchromatography (50% ethyl acetate/hexanes to 100% ethyl acetate) gavethe desired product (3.0 g, 98%) as a single enantiomer. LCMS calculatedfor C₁₉H₁₆BrN₄O₃(M+H)⁺: m/z=427.1, 429.1; found: 426.8, 428.8.

Step 2.(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-9-vinyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one

A mixture of(4S)-9-bromo-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one(3.00 g, 7.02 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane(2.14 mL, 12.6 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (1:1) (570 mg, 0.70 mmol) and potassium carbonate(2.90 g, 21 mmol) in 1,4-dioxane (40 mL) and water (20 mL) was heated at80° C. for 1 h. The mixture was then poured over water and extractedwith ethyl acetate. The extracts were washed with brine, dried oversodium sulfate, filtered and concentrated. Purification by flash columnchromatography (40% ethyl acetate/hexanes to 90% ethyl acetate/hexanes)gave the desired product (1.69 g, 64%) as a single enantiomer. LCMScalculated for C₂₁H₁₉N₄O₃ (M+H)⁺: m/z=375.1; found: 375.1.

Step 3.(4S)-7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-9-carbaldehyde

A mixture of(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-9-vinyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one(1690 mg, 4.51 mmol) in water (7.8 mL) and tetrahydrofuran (104 mL) wastreated with sodium metaperiodate (2.90 g, 13.5 mmol) and heated at 60°C. for 1 h. The reaction mixture was diluted with ethyl acetate andwashed with water and brine, dried over magnesium sulfate, filtered, andconcentrated to give the crude product. Purification by flash columnchromatography (50% ethyl acetate/hexanes to 100% ethyl acetate/hexanes)gave the desired product (0.797 g, 47%) as a single enantiomer. LCMScalculated for C₂₀H₁₇N₄O₄ (M+H)⁺: m/z=377.1; found: 376.9.

Step 4.(4S)-9-{[(2,4-Dimethoxybenzyl)amino]methyl}-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one

A solution(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-9-carbaldehyde(250 mg, 0.664 mmol) in ethanol (12.5 mL) was treated with1-(2,4-dimethoxyphenyl)methanamine [Aldrich #: 432725] (150 μL, 0.996mmol) and acetic acid (20.0 μL, 0.352 mmol) and heated at 60° C. for 1h. The reaction mixture was cooled to room temperature, treated withsodium cyanoborohydride (210 mg, 3.3 mmol) and stirred at roomtemperature for 3 h. The reaction mixture was then quenched with aceticacid (1 mL) and diluted with ethyl acetate. The organic layer was washedwith water and brine, dried over magnesium sulfate, filtered, andconcentrated to give the desired product (0.40 g, 97%) as a singleenantiomer which was used without further purification. LCMS calculatedfor C₂₉H₃₀N₅O₅ (M+H)⁺: m/z=528.2; found: 528.0.

Step 5.(4S)-9-(Aminomethyl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-onebis(trifluoroacetate)

A solution of(4S)-9-{[(2,4-dimethoxybenzyl)amino]methyl}-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one(70.0 mg, 0.133 mmol) in trifluoroacetic acid (5 mL) and water (30 μL)was heated in the microwave at 120° C. for 10 min. The reaction mixturewas concentrated to give a crude residue. Purification via preparativeLCMS (XBridge C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% trifluoroacetic acid, at flow rate of 60 mL/min) gavethe desired product (66 mg, 82%) as a single enantiomer. ¹H NMR (300MHz, DMSO-d₆) δ 11.28 (s, 1H), 8.48 (d, J=4.4 Hz, 1H), 8.18 (br s, 2H),7.80 (ddd, J=7.7, 7.7, 1.7 Hz, 1H), 7.32 (dd, J=7.1, 5.0 Hz, 1H), 7.19(d, J=7.9 Hz, 1H), 6.94 (s, 1H), 5.59 (s, 1H), 4.89-4.73 (m, 1H), 4.44(dd, J=11.5, 3.0 Hz, 1H), 4.13 (d, J=5.5 Hz, 2H), 2.24 (s, 3H), 2.07 (s,3H); LCMS calculated for C₂₀H₂₀N₅O₃ (M+H)⁺: m/z=378.2; found: 378.0.

Example 138N-{[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-9-yl]methyl}acetamidetrifluoroacetate

A solution of(4S)-9-(aminomethyl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-onebis(trifluoroacetate) (10.0 mg, 0.0265 mmol) in methylene chloride (1.00mL) was treated with N,N-diisopropylethylamine (13.8 μL, 0.0795 mmol)followed by acetyl chloride (2.26 μL, 0.0318 mmol) and stirred at roomtemperature for 1 h. The reaction mixture was concentrated to give acrude residue. Purification via preparative LCMS (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1%trifluoroacetic acid, at a flow rate of 60 mL/min) gave the desiredproduct (9 mg, 81%) as a single enantiomer. ¹H NMR (500 MHz, DMSO-d₆) δ10.89 (s, 1H), 8.52 (d, J=4.1 Hz, 1H), 8.31 (dd, J=5.7, 5.7 Hz, 1H),7.79 (ddd, J=7.7, 7.7, 1.8 Hz, 1H), 7.41-7.27 (m, 1H), 7.14 (d, J=7.9Hz, 1H), 6.70 (s, 1H), 5.53 (dd, J=2.4, 2.4 Hz, 1H), 4.76 (dd, J=11.5,2.0 Hz, 1H), 4.41 (dd, J=11.5, 3.1 Hz, 1H), 4.32 (d, J=5.8 Hz, 2H), 2.22(s, 3H), 2.05 (s, 3H), 1.87 (s, 3H); LCMS calculated for C₂₂H₂₂N₅O₄(M+H)⁺: m/z=420.2; found: 420.0.

Examples 139-143

Examples 139 to 142 of Table 7 were synthesized as single enantiomersaccording to the procedure of Example 138.

Example 143 of Table 7 was synthesized according to the procedure ofExample 128, Step 2.

TABLE 7

Ex. No. Name R 139 N-{[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-1,2,4,5- tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-9-yl]methyl}-2- phenylacetamide

140 N-{[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-1,2,4,5- tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-9-yl]methyl}-2- methoxyacetamide

141 N-{[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-1,2,4,5- tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-9- yl]methyl}methanesulfonamide

142 N-{[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-1,2,4,5- tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-9-yl]methyl}- N′-isopropylurea

143 2-(Dimethylamino)-N-{[(4S)-7- (3,5-dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-1,2,4,5- tetrahydroimidazo[1,5,4- de][1,4]benzoxazin-9-yl]methyl}acetamide

Example 144A(4S)-7-(3,5-dimethylisoxazol-4-yl)-9-(1-hydroxyethyl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one(Diastereoisomer 1) Example 144B(4S)-7-(3,5-dimethylisoxazol-4-yl)-9-(1-hydroxyethyl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one(Diastereoisomer 2)

A solution of(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-9-carbaldehyde(1.30 g, 3.45 mmol) (single enantiomer from Example 137, step 3) intetrahydrofuran (30.0 mL) was treated with 3.0 M methylmagnesium iodidein diethyl ether (4.03 mL, 12.1 mmol) and stirred at room temperaturefor 30 min. The reaction mixture was diluted with ethyl acetate, washedwith water and brine, dried over magnesium sulfate, filtered, andconcentrated to give the crude product. Purification by preparative LCMS(XBridge C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% ammonium hydroxide, at flow rate of 60 mL/min) gave thedesired product as a mixture of diastereoisomers. The diastereoisomerswere separated by chiral HPLC (Chiracel AD-H column, 20×250 mm, 5 micronparticle size, eluting with 50% ethanol in hexanes at 12 mL/min, 45 mgper injection) to give Peak 1 (Diastereoisomer 1, RT=10.2 min) and Peak2 (Diastereoisomer 2, RT=12.6 min).

Diastereoisomer 1, Peak 1: ¹H NMR (400 MHz, DMSO-d₆) δ 11.03 (br s, 1H),8.51 (d, J=4.7 Hz, 1H), 7.78 (ddd, J=7.7, 7.7, 1.6 Hz, 1H), 7.31 (dd,J=7.3, 5.0 Hz, 1H), 7.09 (d, J=7.9 Hz, 1H), 6.83 (s, 1H), 5.52 (s, 1H),5.21 (br s, 1H), 4.95 (q, J=6.3 Hz, 1H), 4.76 (dd, J=11.4, 1.5 Hz, 1H),4.42 (dd, J=11.4, 3.0 Hz, 1H), 2.22 (s, 3H), 2.05 (s, 3H), 1.37 (d,J=6.4 Hz, 3H); LCMS calculated for C₂₁H₂₁N₄O₄ (M+H)⁺: m/z=393.2; found:393.0.

Diastereoisomer 2, Peak 2: ¹H NMR (400 MHz, DMSO-d₆) δ 10.97 (br s, 1H),8.52 (d, J=4.7 Hz, 1H), 7.78 (ddd, J=7.7, 7.7, 1.4 Hz, 1H), 7.32 (dd,J=7.4, 4.9 Hz, 1H), 7.11 (d, J=7.8 Hz, 1H), 6.80 (s, 1H), 5.50 (s, 1H),5.20 (br s, 1H), 4.92 (q, J=6.3 Hz, 1H), 4.75 (dd, J=11.4, 1.7 Hz, 1H),4.39 (dd, J=11.4, 3.0 Hz, 1H), 2.23 (s, 3H), 2.06 (s, 3H), 1.40 (d,J=6.4 Hz, 3H); LCMS calculated for C₂₁H₂₁N₄O₄ (M+H)⁺: m/z=393.2; found:393.1.

Example 145(3R)-1-[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]-N-isopropylpyrrolidine-3-carboxamide

Step 1. (3R)—N-Isopropylpyrrolidine-3-carboxamide

To (3R)-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (150 mg,0.70 mmol) in N,N-dimethylformamide (3.0 mL), N,N-diisopropylethylamine(0.25 mL, 1.4 mmol) and 1-hydroxybenzotriazole (94 mg, 0.70 mmol) wereadded. The mixture was stirred at room temperature for 5 min, followedby addition of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride (150 mg, 0.77 mmol). The mixture was then stirred for 20min. 2-Propanamine (59 μL, 0.69 mmol) was added and the mixture wasstirred overnight. The mixture was then diluted with ethyl acetate andwashed with saturated aqueous sodium bicarbonate. The aqueous layer wasseparated and extracted with additional ethyl acetate. The combinedorganic layers were dried over magnesium sulfate, concentrated, andpurified by preparative LCMS using pH 2 buffer to give desiredboc-protected intermediate. The product fractions were concentrated andtreated with 4.0 M hydrogen chloride in 1,4-dioxane (2.0 mL) for 30 min,at which time the mixture was concentrated and dissolved in DCM/MeOH andtreated with Trisamine resin (Silicycle) for 30 min. The resultingmixture was filtered and the solvents were evaporated to give thedesired compound (63 mg, 58%) which was used in the next step withoutfurther purification. LCMS calc. for C₈H₁₇N₂O (M+H)⁺: m/z=157.1; found:157.2.

Step 2.(3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]-N-isopropylpyrrolidine-3-carboxamide

Triethylamine (110 μL, 0.79 mmol) and(3R)—N-isopropylpyrrolidine-3-carboxamide (120 mg, 0.74 mmol) were addedto a solution of(4S)-2-chloro-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine(66.0 mg, 0.18 mmol) in N-methylpyrrolidinone (1.5 mL), and theresulting mixture was heated in a microwave at 120° C. for 5 min. Themixture was diluted with methanol and purified twice by preparative LCMSusing pH 10 buffer to give the title compound, (8.9 mg, 10%). LCMS calc.for C₂₇H₃₁N₆O₃ (M+H)⁺: m/z=487.2; found: 487.3. ¹H NMR (500 MHz, DMSO) δ8.54 (dd, J=4.8, 0.8 Hz, 1H), 7.79 (d, J=7.6 Hz, 1H), 7.72 (td, J=7.7,1.8 Hz, 1H), 7.29 (dd, J=6.8, 4.9 Hz, 1H), 6.95 (d, J=8.1 Hz, 1H), 6.80(d, J=8.1 Hz, 1H), 6.60 (d, J=7.9 Hz, 1H), 6.09 (t, 1H), 4.82 (dd,J=11.4, 1.3 Hz, 1H), 4.53 (dd, J=11.5, 2.8 Hz, 1H), 3.85-3.71 (m, 3H),3.43 (dd, J=9.6, 7.6 Hz, 1H), 3.39-3.32 (m, 1H), 2.90 (p, J=7.8 Hz, 1H),2.19 (s, 3H), 2.02 (s, 3H), 2.00-1.89 (m, 2H), 1.01 (dd, J=10.1, 6.6 Hz,6H).

Example 146A1-[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]-3-methylpyrrolidin-3-ol(Diastereoisomer 1) Example 146B1-[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]-3-methylpyrrolidin-3-ol(Diastereoisomer 2) Example 146C1-[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]-3-methylpyrrolidin-3-ol(Mixture of diastereoisomers)

Triethylamine (0.76 mL, 5.5 mmol) and 3-methylpyrrolidin-3-olhydrochloride (563 mg, 4.09 mmol) were added to(4S)-2-chloro-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine(100 mg, 0.27 mmol) in N-methylpyrrolidinone (3 mL) and the resultingmixture was heated in a microwave at 150° C. for 20 min. The mixture wasthen diluted with methanol and purified by preparative LCMS at pH 2buffer followed by preparative LCMC at pH 10 buffer to give the titlecompound as a mixture of diastereomers (47.1 mg, 40%). LCMS calc. forC₂₄H₂₆N₅O₃ (M+H)⁺: m/z=432.2; found: 432.2. The isomers were separatedby prep chiral column chromatography: Column: phenomenex Lux CelluloseC-2 5 μm, 21, 2×250 mm, Mobile phase: 20% EtOH/Hexanes, gradientcondition: isocratic at 18 mL/min, run time: 30 min, peak time: 23.0 and25.7 min.

Example 146A, Peak 1, 12.6 mg, 11%, LCMS calc. for C₂₄H₂₆N₅O₃ (M+H)⁺:m/z=432.2; found: 432.2.

Example 146B, Peak 2, 12.6 mg, 11%, LCMS calc. for C₂₄H₂₆N₅O₃ (M+H)⁺:m/z=432.2; found: 432.2.

Example 1474-[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]-1,4-diazepane-1-sulfonamide

Step 1. tert-Butyl4-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]-1,4-diazepane-1-carboxylate

The title compound was prepared by methods analogous to Example 146,substituting with tert-butyl 1,4-diazepane-1-carboxylate. The mixturewas concentrated and purified by preparative LCMS using pH 10 buffer togive the title compound (63 mg, 36%). LCMS calc. for C₂₉H₃₅N₆O₄ (M+H)⁺:m/z=531.3; found: 531.3.

Step 2.(4S)-2-(1,4-Diazepan-1-yl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine

tert-Butyl4-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]-1,4-diazepane-1-carboxylate(53 mg, 0.10 mmol) was treated with a solution of 4.0 M hydrogenchloride in 1,4-dioxane (2.0 mL) for 10 min. The mixture wasconcentrated and purified by preparative LCMS using pH 10 buffer to givethe title compound (28.5 mg, 66%). LCMS calc. for C₂₄H₂₇N₆O₂ (M+H)⁺:m/z=431.2; found: 431.3.

Step 3.4-[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]-1,4-diazepane-1-sulfonamide

(4S)-2-(1,4-diazepan-1-yl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine(5.8 mg, 0.013 mmol) and sulfamide (7.8 mg, 0.081 mmol) were dissolvedin pyridine (0.71 mL) and the solution was heated at 120° C. for 3 minin a microwave. The mixture was diluted with methanol and purified bypreparative LCMS using pH 10 buffer to give the title compound (5.1 mg,74%). LCMS calc. for C24H₂₇N₇O₄S (M+H)⁺: m/z=510.2; found: 509.7.

Example 148(4S)-2-(4-Acetyl-1,4-diazepan-1-yl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine

To a solution of(4S)-2-(1,4-diazepan-1-yl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine(5.0 mg, 0.012 mmol) in methylene chloride (0.44 mL), triethylamine (8.1μL, 0.058 mmol) was added followed by acetyl chloride (1.6 μL, 0.023mmol) and the mixture was stirred for 5 min. The mixture was thendiluted with methanol and purified by preparative LCMS using pH 10buffer to give the title compound (3.5 mg, 64%). LCMS calc. forC₂₆H₂₉N₆O₃ (M+H)⁺: m/z=473.2; found: 473.3.

Example 149(4S)-7-(3,5-Dimethylisoxazol-4-yl)-2-[4-(methylsulfonyl)-1,4-diazepan-1-yl]-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine

Triethylamine (8.1 μL, 0.058 mmol) was added to a solution of(4S)-2-(1,4-diazepan-1-yl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine(5.0 mg, 0.012 mmol) in methylene chloride (0.44 mL), and the mixturewas cooled to 0° C. Methanesulfonyl chloride (1.8 μL, 0.023 mmol) wasthen added and the mixture was stirred for 5 min at 0° C. The mixturewas diluted with methanol and purified by preparative LCMS using pH 10buffer to give the title compound (3.8 mg, 64%). LCMS calc. forC₂₅H₂₉N₆O₄S (M+H)⁺: m/z=509.2; found: 509.2.

Example 150(4S)-7-(3,5-Dimethylisoxazol-4-yl)-2-piperazin-1-yl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazinetrihydrochloride

Step 1. tert-Butyl4-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperazine-1-carboxylate

The title compound was prepared by methods analogous to Example 146,substituting tert-butyl piperazine-1-carboxylate. The mixture wasconcentrated and purified by preparative LCMS using pH 10 buffer to givethe product. LCMS calc. for C₂₈H₃₃N₆O₄ (M+H)⁺: m/z=517.3; found: 517.4.

Step 2.(4S)-7-(3,5-Dimethylisoxazol-4-yl)-2-piperazin-1-yl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazinetrihydrochloride

tert-Butyl4-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperazine-1-carboxylate(45 mg, 0.087 mmol) was stirred in 4 N HCl in dioxanes (3 mL) andmethanol (2 mL) for 30 min, at which time the solvent was evaporated togive the title compound (45 mg, 92%). LCMS calc. for C₂₇H₃₂N₇O₃ (M+H)⁺:m/z=417.2; found: 417.3.

Example 1512-{4-[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperazin-1-yl}-N,N-dimethylacetamide

To a solution of(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-piperazin-1-yl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazinetrihydrochloride (10 mg, 0.03 mmol) in methylene chloride (1.0 mL),potassium carbonate (18 mg, 0.13 mmol) was added, followed by2-chloro-N, N-dimethylacetamide (2.7 μL, 0.026 mmol) and the mixture wasstirred for 5 min. The mixture was then heated at 60° C. overnight. Themixture was diluted with methanol and purified by preparative LCMS usingpH 10 buffer to give the title compound, (3.7 mg, 30%). LCMS calc. forC₂₇H₃₂N₇O₃ (M+H)⁺: m/z=502.2; found: 502.3.

Example 1522-Cyano-N-{(3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-yl}-N-methylacetamide

Triethylamine (8.2 μL, 0.059 mmol) and ethanol (1.0 mL) were added to asolution of(3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]-N-methylpyrrolidin-3-amine(8.5 mg, 0.020 mmol) in methylene chloride (0.50 mL), followed byaddition of 3-[(2,5-dioxopyrrolidin-1-yl)oxy]-3-oxopropanenitrile (7.2mg, 0.039 mmol) and the mixture was stirred overnight at roomtemperature. The mixture was then diluted with methanol and purified bypreparative LCMS using pH 10 buffer to give the title compound (1.4 mg,14%). LCMS calc. for C₂₇H₂₈N₇O₃ (M+H)⁺: m/z=498.2; found: 498.3.

Example 153N-{(3R)-1-[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-yl}morpholine-4-carboxamide

To a solution of(3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-aminetrihydrochloride (35 mg, 0.068 mmol) in methylene chloride (1.0 mL),triethylamine (18 μL, 0.13 mmol) was added followed bymorpholine-4-carbamoyl chloride (10 μL, 0.1 mmol) and the mixture wasstirred for 5 min. The mixture was diluted with methanol and purified bypreparative LCMS using pH 10 buffer to give the title compound, (4.1 mg,30%). LCMS calc. for C₂₈H₃₂N₇O₄ (M+H)⁺: m/z=530.2; found: 530.3.

Example 1547-(3,5-Dimethylisoxazol-4-yl)-2-methyl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine

A mixture of2-chloro-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine(45 mg, 0.12 mmol), 2.0 M methylzinc chloride in THF (310 μL), andtetrakis(triphenylphosphine)palladium(0) (7 mg, 0.006 mmol) in THF (2mL) under nitrogen was heated in a microwave at 150° C. for 5 min.Purification by preparative LCMS using pH 10 buffer gave the titlecompound (21 mg, 49%). LCMS calc. for C₂₀H₁₉N₄O₂ (M+H)⁺: m/z=347.1;found: 347.2. ¹H NMR (300 MHz, CD₃OD) δ 8.58 (d, J=4.8 Hz, 1H), 7.69(td, J=7.8, 1.8 Hz, 1H), 7.32 (dd, J=7.1, 5.3 Hz, 1H), 7.05 (d, J=8.1Hz, 2H), 6.89 (d, J=8.1 Hz, 2H), 6.59 (d, J=7.9 Hz, 1H), 6.03 (s, 1H),4.55 (dd, J=11.5, 2.8 Hz, 2H), 4.29-4.09 (m, 1H), 4.00-3.71 (m, 2H),3.63-3.50 (m, 3H), 3.40 (dd, J=9.8, 4.6 Hz, 1H), 2.23 (s, 3H), 2.23-2.11(m, 1H), 2.08 (s, 3H), 1.98-1.83 (m, 1H).

Example 155 Methyl{(3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-yl}carbamate

Step 1.(3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-aminetrihydrochloride

(4S)-2-Chloro-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine(300 mg, 0.8 mmol) tert-butyl (3R)-pyrrolidin-3-ylcarbamate (4.57 g,24.5 mmol) and triethylamine (570 μL, 4.1 mmol) were stirred inN-methylpyrrolidinone (10 mL) and heated to 150° C. in a microwave for 5min. Purification by preparative LCMS (pH 10) gave the desiredboc-protected intermediate. Treatment with 4 N HCl in dioxanes/methanoland subsequent evaporation of the solvents afforded the title compound(36 mg, 100%). LCMS calc. for C₂₃H₂₅N₆O₂ (M+H)⁺: m/z=417.2; found:417.3.

Step 2. Methyl{(3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-yl}carbamate

(3R)-1-[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-aminetrihydrochloride (35 mg, 0.068 mmol) was stirred in methylene chloride(1.0 mL) with triethylamine (47 μL, 0.34 mmol), followed by addition ofmethyl chloroformate (10 μL, 0.14 mmol). The mixture was stirred at roomtemperature for 30 min and concentrated. Purification by preparativeLCMS using pH 10 buffer gave the title compound (24 mg, 75%). LCMS calc.for C₂₅H₂₇N₆O₄ (M+H)⁺: m/z=475.2; found: 475.3. ¹H NMR (300 MHz, CD₃OD)δ 8.58 (d, J=4.8 Hz, 1H), 7.69 (td, J=7.8, 1.8 Hz, 1H), 7.32 (dd, J=7.1,5.3 Hz, 1H), 7.05 (d, J=8.1 Hz, 2H), 6.89 (d, J=8.1 Hz, 2H), 6.59 (d,J=7.9 Hz, 1H), 6.03 (s, 1H), 4.55 (dd, J=11.5, 2.8 Hz, 2H), 4.29-4.09(m, 1H), 4.00-3.71 (m, 2H), 3.63-3.50 (m, 3H), 3.40 (dd, J=9.8, 4.6 Hz,1H), 2.23 (s, 3H), 2.23-2.11 (m, 1H), 2.08 (s, 3H), 1.98-1.83 (m, 1H).

Example 1567-(3,5-Dimethylisoxazol-4-yl)-9-fluoro-N,N-dimethyl-4-pyridin-3-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-amine

Step 1. 6-Bromo-4-fluoro-2,3-dinitrophenol

To a solution of 2-bromo-4-fluoro-5-nitrophenol (4.0 g, 17 mmol) inmethylene chloride (29.5 mL), 2.0 M nitric acid in DCM (25 mL) was addedand the mixture was stirred for 15 min at room temperature. The mixturewas poured over cold water and extracted with methylene chloride to givethe product.

Step 2. 2-Amino-6-bromo-4-fluoro-3-nitrophenol

6-Bromo-4-fluoro-2,3-dinitrophenol (4.4 g, 16 mmol) was stirred inmethanol (88 mL) and 12.0 M hydrogen chloride in water (40 mL), followedby addition of stannous chloride dihydrate (11 g, 47 mmol) and themixture was stirred at room temperature for 15 min. The mixture wasdiluted with water and extracted with ethyl acetate. The organic layerwas separated and concentrated. Purification on silica gel eluting ethylacetate in hexanes gave the amine product.

Step 3.8-Bromo-6-fluoro-5-nitro-3-pyridin-3-yl-3,4-dihydro-2H-1,4-benzoxazin-3-ol

2-Amino-6-bromo-4-fluoro-3-nitrophenol (500 mg, 2.0 mmol) and potassiumcarbonate (780 mg, 5.7 mmol) were stirred in acetone (8 mL) for 15 minfollowed by addition of 2-bromo-1-pyridin-3-ylethanone hydrobromide (530mg, 1.9 mmol) over a period of 5 min. The mixture was stirred at roomtemperature for 15 min and poured over water. The aqueous mixture wasextracted with ethyl acetate. The organic extracts were washed withbrine, dried over sodium sulfate, filtered, and concentrated.Purification on silica gel elucting ethyl acetate in hexanes affordedthe bicyclic product. LCMS calc. for C₁₃H₁₀BrFN₃O₄(M+H)⁺: m/z=370.0;found: 370.0.

Step 4. 8-Bromo-6-fluoro-3-pyridin-3-yl-2H-1,4-benzoxazin-5-amine

Iron (91 mg, 1.6 mmol) was added to a mixture of8-bromo-6-fluoro-5-nitro-3-pyridin-3-yl-3,4-dihydro-2H-1,4-benzoxazin-3-ol(121.0 mg, 0.3269 mmol) in acetic acid (3 mL), and heated overnight at60° C. The mixture was extracted with ethyl acetate and the organiclayer concentrated. Purification on silica gel eluting ethyl acetate inhexanes afforded product. LCMS calc. for C₁₃H₁₀BrFN₃O (M+H)⁺: m/z=322.0;found: 322.0.

Step 5.8-Bromo-6-fluoro-3-pyridin-3-yl-3,4-dihydro-2H-1,4-benzoxazin-5-amine

Sodium tetrahydroborate (44 mg, 1.2 mmol) was added to a solution of8-bromo-6-fluoro-3-pyridin-3-yl-2H-1,4-benzoxazin-5-amine (190 mg, 0.58mmol) in ethanol (4 mL) and water (1 mL), and heated at 90° C. for 15minutes. The mixture was concentrated, diluted with water, and extractedwith ethyl acetate. The organic solvents were evaporated to afford theproduct. LCMS calc. for C₁₃H₁₂BrFN₃O (M+H)⁺: m/z=324.0; found: 324.0.

Step 6.7-Bromo-9-fluoro-4-pyridin-3-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one

Triethylamine (140 μL, 1.0 mmol) was added to a solution of8-bromo-6-fluoro-3-pyridin-3-yl-3,4-dihydro-2H-1,4-benzoxazin-5-amine(160 mg, 0.50 mmol)) in THF (6.0 mL), followed by addition oftriphosgene (60 mg, 0.2 mmol), and the mixture was subsequently stirredat room temperature for 10 min. The mixture was diluted with water andextracted with ethyl acetate. The organic extracts were washed withbrine and concentrated. Purification on silica gel eluting ethyl acetatein hexanes afforded the title compound. LCMS calc. forC₁₄H₁₀BrFN₃O₂(M+H)⁺: m/z=350.0; found: 350.0.

Step 7.7-(3,5-Dimethylisoxazol-4-yl)-9-fluoro-4-pyridin-3-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one

7-Bromo-9-fluoro-4-pyridin-3-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one(50 mg, 0.14 mmol), potassium(3,5-dimethylisoxazol-4-yl)(trifluoro)borate(1-) (43 mg, 0.21 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (1:1) (10 mg, 0.01 mmol) and potassium carbonate(39 mg, 0.28 mmol) were stirred in 1,4-dioxane (1.1 mL) and water (0.28mL) under a flow of nitrogen gas for 5 min. The mixture was then heatedto 90° C. for 6 h. The mixture was diluted with water and extracted withethyl acetate. The organic extracts were collected and evaporated togive the desired compound. LCMS calc. for C₁₉H₁₆FN₄O₃(M+H)⁺: m/z=367.1;found: 367.1.

Step 8.2-Chloro-7-(3,5-dimethylisoxazol-4-yl)-9-fluoro-4-pyridin-3-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine

Phosphoryl chloride (1.5 mL, 16 mmol) was added to a vial charged with7-(3,5-dimethylisoxazol-4-yl)-9-fluoro-4-pyridin-3-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one(32 mg, 0.087 mmol) and the mixture was stirred overnight at 90° C. Themixture was quenched with ice-cold water, diluted with NaHCO₃ andextracted with ethyl acetate. The organic extracts were collected andevaporated to afford the title compound. LCMS calc. for C₁₉H₁₅ClFN₄O₂(M+H)⁺: m/z=385.1; found: 385.1.

Step 9.7-(3,5-Dimethylisoxazol-4-yl)-9-fluoro-N,N-dimethyl-4-pyridin-3-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-amine

Triethylamine (16 μL, 0.12 mmol) and dimethylamine (0.2 mL, 4 mmol) wereadded to2-chloro-7-(3,5-dimethylisoxazol-4-yl)-9-fluoro-4-pyridin-3-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine(15 mg, 0.040 mmol) in N-methylpyrrolidinone (0.41 mL) and the mixturewas heated in a microwave at 150° C. for 20 min. The mixture was dilutedwith methanol and purified by preparative LCMS using pH 10 buffer toafford the title compound (3.0 mg, 19%). LCMS calc. for C₂₁H₂₁FN₅O₅₂(M+H): m/z=394.2; found: 394.1.

Example 1571-[7-(3,5-Dimethylisoxazol-4-yl)-9-fluoro-4-pyridin-3-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-ol

Triethylamine (16 μL, 0.12 mmol) and 3-pyrrolidinol (0.2 mL, 3 mmol)were added to2-chloro-7-(3,5-dimethylisoxazol-4-yl)-9-fluoro-4-pyridin-3-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine(15 mg, 0.040 mmol) in N-methylpyrrolidinone (0.41 mL) and the mixturewas heated in a microwave at 150° C. for 20 min. The mixture was dilutedwith methanol and purified by preparative LCMS using pH 10 buffer toafford the title compound (2.4 mg, 14%). LCMS calc. forC₂₃H₂₃FN₅O₃(M+H)⁺: m/z=436.2; found: 436.1.

Example 1587-(3,5-Dimethylisoxazol-4-yl)-N-ethyl-9-fluoro-4-pyridin-3-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-amine

Triethylamine (16 μL, 0.12 mmol) and ethylamine (0.2 mL, 3 mmol) wereadded to2-chloro-7-(3,5-dimethylisoxazol-4-yl)-9-fluoro-4-pyridin-3-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine(15 mg, 0.040 mmol) in N-methylpyrrolidinone (0.41 mL) and the mixturewas heated in a microwave at 150° C. for 20 min. The mixture was dilutedwith methanol and purified by preparative LCMS using pH 10 buffer toafford the title compound (3.0 mg, 19%). LCMS calc. for C₂₁H₂₁FN₅O₂(M+H)⁺: m/z=394.2; found: 394.1.

Example 159A(3R)-1-[7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-3-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-ol(Diastereoisomer 1) Example 159B(3R)-1-[7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-3-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-ol(Diastereoisomer 2A) Example 159C(3R)-1-[7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-3-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-ol(Diastereoisomer 2B) Example 159D(3R)-1-[7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-3-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-ol(Diastereoisomer 3) Example 159E(3R)-1-[7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-3-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-ol(Mixture of Diastereoisomers)

The title compound was prepared by methods analogous to Example 157,substituting2-chloro-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-3-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazineand 3R-pyrrolidinol. The mixture was diluted with methanol and purifiedby preparative LCMS using pH 10 buffer to afford the title compound as amixture of diastereomers (13.3 mg, 75%). LCMS calc. for C₂₃H₂₄N₅O₃(M+H)⁺: m/z=418.2; found: 418.2. The isomers were separated by prepchiral column chromatography using the following conditions: Column:phenomenex Lux Cellulose C-2 5 μm, 21, 2×250 mm, Mobile phase: 45%EtOH/Hexanes, gradient condition: isocratic at 18 mL/min, Loading: 5.0mg in 900 μL, run time: 18 min, peak time: 12.0, 14.0 and 16.0 min.

Example 159A, Peak 1, LCMS calc. for C₂₃H₂₄N₅O₃ (M+H)⁺: m/z=418.2;found: 418.2.

Peak 2 was isolated as a mixture of 2 diastereomers and furtherseparated by prep chiral column chromatography: Column: phenomenex LuxCellulose C-4 5 μm, 21, 2×250 mm, Mobile phase: 30% EtOH/Hexanes,gradient condition: isocratic at 18 mL/min, Loading: 1.5 mg in 900 μL,run time: 23 min, peak time: 18.5 and 20.0 min.

Example 159B, Peak 2A, LCMS calc. for C₂₃H₂₄N₅O₃ (M+H)⁺: m/z=418.2;found: 418.2.

Example 159C, Peak 2B, LCMS calc. for C₂₃H₂₄N₅O₃ (M+H)⁺: m/z=418.2;found: 418.2.

Example 159D, Peak 3, LCMS calc. for C₂₃H₂₄N₅O₃ (M+H)⁺: m/z=418.2;found: 418.2.

Examples 160A1-[7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-3-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]azetidin-3-olExamples 160B1-[7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-3-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]azetidin-3-olExamples 160C1-[7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-3-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]azetidin-3-olExamples 160D1-[7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-3-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]azetidin-3-ol

The title compound was prepared by methods analogous to Example 157,substituting2-chloro-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-3-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine,azetidin-3-ol hydrochloride and extending the reaction time to 60 min.The mixture was diluted with methanol and purified by preparative LCMSusing pH 10 buffer to give the title compound as a racemic mixture (16mg, 23%). LCMS calc. for C₂₂H₂₂N₅O₃ (M+H)⁺: m/z=404.2; found: 404.2. Theisomers were separated by prep chiral column chromatography using thefollowing conditions: Column: phenomenex Lux Cellulose C-2 5 μm, 21,2×250 mm, Mobile phase: 45% EtOH/Hexanes, gradient condition: isocraticat 18 mL/min, Loading: 2.0 mg in 900 μL, run time: 24 min, peak time:12.0, 14.0, 16.0 and 21.0 min.

Example 160A, Peak 1, LCMS calc. for C₂₂H₂₂N₅O₃ (M+H)⁺: m/z=404.2;found: 404.2. ¹H NMR (500 MHz, DMSO) δ 8.47 (dd, J=4.8, 1.6 Hz, 1H),8.43 (d, J=2.2 Hz, 1H), 7.58 (dt, J=7.9, 1.9 Hz, 1H), 7.35 (dd, J=7.9,4.8 Hz, 1H), 6.74 (d, J=7.9 Hz, 1H), 6.70 (d, J=8.0 Hz, 1H), 5.42 (t,1H), 5.07 (d, J=3.8 Hz, 1H), 4.61 (dd, J=11.6, 1.9 Hz, 1H), 4.36 (dd,J=11.6, 2.9 Hz, 1H), 4.00 (d, J=3.5 Hz, 1H), 3.91 (dd, J=11.5, 2.8 Hz,1H), 3.67 (dd, J=11.5, 4.2 Hz, 1H), 3.40-3.34 (m, 1H), 3.17 (dd, J=14.3,4.2 Hz, 1H), 2.24 (s, 3H), 2.07 (s, 3H).

Example 160B, Peak 2, LCMS calc. for C₂₂H₂₂N₅O₃ (M+H)⁺: m/z=404.2;found: 404.2. ¹H NMR (500 MHz, DMSO) δ 8.47 (dd, J=4.8, 1.6 Hz, 1H),8.43 (d, J=2.2 Hz, 1H), 7.58 (dt, J=7.9, 1.9 Hz, 1H), 7.35 (dd, J=7.9,4.8 Hz, 1H), 6.74 (d, J=7.9 Hz, 1H), 6.70 (d, J=8.0 Hz, 1H), 5.42 (t,1H), 5.07 (d, J=3.8 Hz, 1H), 4.61 (dd, J=11.6, 1.9 Hz, 1H), 4.36 (dd,J=11.6, 2.9 Hz, 1H), 4.00 (d, J=3.5 Hz, 1H), 3.91 (dd, J=11.5, 2.8 Hz,1H), 3.67 (dd, J=11.5, 4.2 Hz, 1H), 3.40-3.34 (m, 1H), 3.17 (dd, J=14.3,4.2 Hz, 1H), 2.24 (s, 3H), 2.07 (s, 3H).

Example 160C, Peak 3, LCMS calc. for C₂₂H₂₂N₅O₃ (M+H)⁺: m/z=404.2;found: 404.2. ¹H NMR (500 MHz, DMSO) δ 8.47 (dd, J=4.8, 1.6 Hz, 1H),8.43 (d, J=2.2 Hz, 1H), 7.58 (dt, J=7.9, 1.9 Hz, 1H), 7.35 (dd, J=7.9,4.8 Hz, 1H), 6.74 (d, J=7.9 Hz, 1H), 6.70 (d, J=8.0 Hz, 1H), 5.42 (t,1H), 5.07 (d, J=3.8 Hz, 1H), 4.61 (dd, J=11.6, 1.9 Hz, 1H), 4.36 (dd,J=11.6, 2.9 Hz, 1H), 4.00 (d, J=3.5 Hz, 1H), 3.91 (dd, J=11.5, 2.8 Hz,1H), 3.67 (dd, J=11.5, 4.2 Hz, 1H), 3.40-3.34 (m, 1H), 3.17 (dd, J=14.3,4.2 Hz, 1H), 2.24 (s, 3H), 2.07 (s, 3H).

Example 160D, Peak 4, LCMS calc. for C₂₂H₂₂N₅O₃ (M+H)⁺: m/z=404.2;found: 404.2. ¹H NMR (500 MHz, DMSO) δ 8.47 (dd, J=4.8, 1.6 Hz, 1H),8.43 (d, J=2.2 Hz, 1H), 7.58 (dt, J=7.9, 1.9 Hz, 1H), 7.35 (dd, J=7.9,4.8 Hz, 1H), 6.74 (d, J=7.9 Hz, 1H), 6.70 (d, J=8.0 Hz, 1H), 5.42 (t,1H), 5.07 (d, J=3.8 Hz, 1H), 4.61 (dd, J=11.6, 1.9 Hz, 1H), 4.36 (dd,J=11.6, 2.9 Hz, 1H), 4.00 (d, J=3.5 Hz, 1H), 3.91 (dd, J=11.5, 2.8 Hz,1H), 3.67 (dd, J=11.5, 4.2 Hz, 1H), 3.40-3.34 (m, 1H), 3.17 (dd, J=14.3,4.2 Hz, 1H), 2.24 (s, 3H), 2.07 (s, 3H).

Examples 161-251

The compounds of Examples 161 to 251 are set out in Table 8 below.

TABLE 8

Ex. No. Name R⁵ Procedure* 161 (4S)-7-(3,5-dimethylisoxazol-4-yl)-2-morpholin-4-yl-4-pyridin-2-yl-4,5- dihydroimidazo[1,5,4-de][1,4]benzoxazine

 25 162 (4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-2-pyrrolidin-1-yl-4,5- dihydroimidazo[1,5,4-de][1,4]benzoxazine

 25 163 (4S)-7-(3,5-dimethylisoxazol-4-yl)-2-(4-methylpiperazin-1-yl)-4-pyridin-2-yl- 4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine

 25 164 (4S)-2-azetidin-1-yl-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl- 4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine

 25 165 1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]azetidin-3-ol

 25 166 4-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazin-2-yl]-1-methylpiperazin-2-one

 25 167 ethyl 4-[(4S)-7-(3,5-dimethylisoxazol-4- yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazin-2-yl]piperazine-1- carboxylate

 25 168A (3R)-1-[(4S)-7-(3,5-Dimethylisoxazol-4- yl)-4-pyridin-3-yl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazin-2-yl]pyrrolidin-3-ol

 25 168B (3S)-1-[(4S)-7-(3,5-Dimethylisoxazol-4- yl)-4-pyridin-3-yl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazin-2-yl]pyrrolidin-3-ol

 25 169 1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperidin-4-ol

 25 170A (3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4- yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazin-2-yl]piperidin-3-ol

 25 170B (3S)-1-[(4S)-7-(3,5-dimethylisoxazol-4- yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazin-2-yl]piperidin-3-ol

 25 171 1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazin-2-yl]-N,N-dimethylpiperidin-4-amine

 25 172 4-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperazin-2-one

 25 173 (4S)-7-(3,5-dimethylisoxazol-4-yl)-2-[4-(methylsulfonyl)piperazin-1-yl]-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazine

 25 174 (4S)-7-(3,5-dimethylisoxazol-4-yl)-2-(4-isopropylpiperazin-1-yl)-4-pyridin-2-yl- 4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine

 25 175 1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperidine-4- carbonitrile

 25 176 {1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperidin-4- yl}methanol

 25 177 2-{4-[(4S)-7-(3,5-dimethylisoxazol-4- yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazin-2-yl]piperazin-1- yl}ethanol

 25 178 (4S)-7-(3,5-dimethylisoxazol-4-yl)-2-(4-phenylpiperazin-1-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[1,5,4-de][1,4]benzoxazine

 25 179 (4S)-2-(4-benzylpiperazin-1-yl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl- 4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine

 25 180A (3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4- yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazin-2-yl]-N,N-dimethylpyrrolidin-3-amine

 25 180B (3S)-1-[(4S)-7-(3,5-dimethylisoxazol-4- yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazin-2-yl]-N,N-dimethylpyrrolidin-3-amine

 25 181A (3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4- yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazin-2-yl]-N-methylpyrrolidin-3-amine

 25 181B (3S)-1-[(4S)-7-(3,5-dimethylisoxazol-4- yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazin-2-yl]-N-methylpyrrolidin-3-amine

 25 182A tert-butyl {(3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl- 4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3- yl}carbamate

 25 182B tert-butyl {(3S)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl- 4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3- yl}carbamate

 25 183 (4S)-2-[4-(cyclopropylmethyl)piperazin-1-yl]-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazine

 25 184 (4S)-7-(3,5-dimethylisoxazol-4-yl)-2-[4-(2-methoxyethyl)piperazin-1-yl]-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazine

 25 185 2-[[7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazin-2-yl](methyl)amino]ethanol

 25 186 7-(3,5-dimethylisoxazol-4-yl)-N-methyl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazin-2-amine

 25 187 7-(3,5-dimethylisoxazol-4-yl)-N,N- dimethyl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazin-2-amine

 25 188 1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperidine-4- carboxamide

 25 189 1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazin-2-yl]-N-methylpiperidine-4-carboxamide

 25 190 N-{1-[(4S)-7-(3,5-dimethylisoxazol-4- yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazin-2-yl]piperidin-4- yl}acetamide

 25 191 2-{4-[(4S)-7-(3,5-dimethylisoxazol-4- yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazin-2-yl]piperazin-1- yl}acetamide

 25 192 (4S)-7-(3,5-dimethylisoxazol-4-yl)-2-(4-ethylpiperazin-1-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[1,5,4-de][1,4]benzoxazine

 25 193A (4S)-7-(3,5-dimethylisoxazol-4-yl)-2-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin- 2(1H)-yl]-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazine

 25 193B (4S)-7-(3,5-dimethylisoxazol-4-yl)-2- [(8aR)-hexahydropyrrolo[1,2-a]pyrazin- 2(1H)-yl]-4-pyridin-2-yl-4,5- dihydroimidazo[1,5,4-de][1,4]benzoxazine

 25 194 1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazin-2-yl]-4-methylpiperidin-4-ol

 25 195 4-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazin-2-yl]-3-methylpiperazin-2-one

 25 196 tert-butyl {1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl- 4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]azetidin-3- yl}carbamate

 25 197 tert-butyl 4-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl- 4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]-1,4-diazepane- 1-carboxylate

 25 198 2-{[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]amino}ethanol

 25 199 tert-butyl (2-{[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl- 4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]amino }ethyl)carbamate

 25 200 N-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]ethane-1,2- diamine

150 201A N-{(3R)-1-[(4S)-7-(3,5- dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazin-2-yl]pyrrolidin-3-yl}acetamide

 25 201B N-{(3S)-1-[(4S)-7-(3,5- dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazin-2-yl]pyrrolidin-3-yl}acetamide

 25 202A (3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4- yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazin-2-yl]pyrrolidin-3- aminetrihydrochloride

150 202B (3S)-1-[(4S)-7-(3,5-dimethylisoxazol-4- yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazin-2-yl]pyrrolidin-3- aminetrihydrochloride

150 203 N-{(3R)-1-[(4S)-7-(3,5- dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazin-2-yl]pyrrolidin-3-yl}-2,2,2-trifluoroacetamide

148 205 N-{(3R)-1-[(4S)-7-(3,5- dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazin-2-yl]pyrrolidin-3-yl}-2-methoxyacetamide

148 206 N-{(3R)-1-[(4S)-7-(3,5- dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazin-2-yl]pyrrolidin-3-yl}cyclopropanecarboxamide

148 207 N-{(3R)-1-[(4S)-7-(3,5- dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazin-2-yl]pyrrolidin-3-yl}methanesulfonamide

149 208 N-{(3R)-1-[(4S)-7-(3,5- dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazin-2-yl]pyrrolidin-3-yl}propanamide

148 209 N-{(3R)-1-[(4S)-7-(3,5- dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazin-2-yl]pyrrolidin-3-yl}-2-methylpropanamide

148 210 N-{(3R)-1-[(4S)-7-(3,5- dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazin-2-yl]pyrrolidin-3-yl}cyclobutanecarboxamide

148 211 2-cyano-N-{(3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl- 4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3- yl}acetamide

152 213 N-{(3R)-1-[(4S)-7-(3,5- dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazin-2-yl]pyrrolidin-3-yl}tetrahydro-2H-pyran-4-carboxamide

148 214 N-{(3R)-1-[(4S)-7-(3,5- dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazin-2-yl]pyrrolidin-3-yl}ethanesulfonamide

149 215 N-{(3R)-1-[(4S)-7-(3,5- dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazin-2-yl]pyrrolidin-3-yl}propane-1-sulfonamide

149 216 N′-{(3R)-1-[(4S)-7-(3,5- dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazin-2-yl]pyrrolidin-3-yl}-N,N-dimethylurea

153 217 N-{(3R)-1-[(4S)-7-(3,5- dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazin-2-yl]pyrrolidin-3-yl}propane-2-sulfonamide

149 218 N-{(3R)-1-[(4S)-7-(3,5- dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazin-2-yl]pyrrolidin-3-yl}cyclopropanesulfonamide

149 219 methyl {(3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl- 4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3- yl}methylcarbamate

155 220 N-{(3R)-1-[(4S)-7-(3,5- dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazin-2-yl]pyrrolidin-3-yl}-N-methylmethanesulfonamide

149 221 N-{(3R)-1-[(4S)-7-(3,5- dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazin-2-yl]pyrrolidin-3-yl}-2-methoxy-N-methylacetamide

148 222 N-{(3R)-1-[(4S)-7-(3,5- dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazin-2-yl]pyrrolidin-3-yl}-N-methylacetamide

148 224 (4S)-2-(4-acetylpiperazin-1-yl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl- 4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine

148 225 (4S)-7-(3,5-dimethylisoxazol-4-yl)-2-(4-propionylpiperazin-1-yl)-4-pyridin-2-yl- 4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine

148 226 (4S)-7-(3,5-dimethylisoxazol-4-yl)-2-[4-(ethylsulfonyl)piperazin-1-yl]-4-pyridin- 2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine

149 228 (4S)-7-(3,5-dimethylisoxazol-4-yl)-2-[4-(2-oxo-2-pyrrolidin-1-ylethyl)piperazin- 1-yl]-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazine

151 229 4-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperazine-1- sulfonamide

147 230 1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]azetidin-3- amine trihydrochloride

150 231 N-{1-[(4S)-7-(3,5-dimethylisoxazol-4- yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazin-2-yl]azetidin-3- yl}acetamide

148 232 N-{1-[(4S)-7-(3,5-dimethylisoxazol-4- yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazin-2-yl]azetidin-3- yl}propanamide

148 233 N-{1-[(4S)-7-(3,5-dimethylisoxazol-4- yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazin-2-yl]azetidin-3-yl}-2-methylpropanamide

148 234 N-{1-[(4S)-7-(3,5-dimethylisoxazol-4- yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazin-2-yl]azetidin-3-yl}-2-methoxyacetamide

148 235 N-{1-[(4S)-7-(3,5-dimethylisoxazol-4- yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazin-2-yl]azetidin-3-yl}cyclopropanecarboxamide

148 236 N-{1-[(4S)-7-(3,5-dimethylisoxazol-4- yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazin-2-yl]azetidin-3-yl}cyclobutanecarboxamide

148 237 N-{1-[(4S)-7-(3,5-dimethylisoxazol-4- yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazin-2-yl]azetidin-3-yl}methanesulfonamide

149 238 N-{1-[(4S)-7-(3,5-dimethylisoxazol-4- yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazin-2-yl]azetidin-3-yl}ethanesulfonamide

149 239 N-{1-[(4S)-7-(3,5-dimethylisoxazol-4- yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazin-2-yl]azetidin-3-yl}propane-2-sulfonamide

149 240 N-{1-[(4S)-7-(3,5-dimethylisoxazol-4- yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazin-2-yl]piperidin-4-yl}methanesulfonamide

149 241 N-{1-[(4S)-7-(3,5-dimethylisoxazol-4- yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazin-2-yl]piperidin-4-yl}-2-methoxyacetamide

149 242 N-{1-[(4S)-7-(3,5-dimethylisoxazol-4- yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazin-2-yl]piperidin-4-yl}-2,2,2-trifluoroacetamide

148 243 N-{1-[(4S)-7-(3,5-dimethylisoxazol-4- yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazin-2-yl]piperidin-4-yl}propanamide

148 244 N-{1-[(4S)-7-(3,5-dimethylisoxazol-4- yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazin-2-yl]piperidin-4-yl}propanamide

148 246 (4S)-7-(3,5-dimethylisoxazol-4-yl)-2-(4-propionyl-1,4-diazepan-1-yl)-4-pyridin- 2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine

148 248 (4S)-7-(3,5-dimethylisoxazol-4-yl)-2-[4-(ethylsulfonyl)-1,4-diazepan-1-yl]-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazine

149 249 (3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4- yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazin-2-yl]-N-methylpyrrolidine-3-carboxamide

145 250 (3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4- yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4- de][1,4]benzoxazin-2-yl]-N-ethylpyrrolidine-3-carboxamide

145 251 (3R)-N-cyclopropyl-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl- 4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidine-3- carboxamide

145 *The number in this column indicates the Example number of theprocedure used to prepare the compound.

Example 252(4S)-8,9-dichloro-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-onebistrifluoroacetate

A mixture of(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one(35 mg, 0.10 mmol) N-chlorosuccinimide (15 mg, 0.11 mmol) andtetrahydrofuran (1.0 mL) was stirred at 60° C. for 3 hrs. The mixturewas extracted with EtOAc, dried, concentrated, purified on silicagel andeluted with 40% EtOAc in hexane. Purification by preparative LCMS usingpH 2 buffer gave the title compound as a bistrifluoroacetate salt. LCMScalc. for C₁₉H₁₅C₁₂N₄O₃ (M+H)⁺: m/z=417.0; found: 417.2.

Example 2537-(3,5-Dimethylisoxazol-4-yl)-9-[(isopropylamino)methyl]-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one

7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-9-carbaldehyde(15 mg, 0.04 mmol) from Example 137, Step 3 was stirred in methanol (1.0mL) with 2-propanamine (10. L, 0.12 mmol), followed by addition ofsodium cyanoborohydride (7.5 mg, 0.12 mmol). The mixture was heated at60° C. overnight, then diluted with methanol. Purification bypreparative LCMS (pH 10) afforded the title compound. LCMS calc. forC₂₃H₂₆N₅O₃ (M+H)⁺: m/z=420.2; found: 420.1.

Example 2547-(3,5-Dimethylisoxazol-4-yl)-9-(hydroxymethyl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one

7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-9-carbaldehyde(15 mg, 0.040 mmol) from Example 137, Step 3 was stirred in ethanol(0.58 mL), followed by addition of sodium tetrahydroborate (2.3 mg,0.060 mmol). The mixture was stirred at room temperature for 1 h.Purification by preparative LCMS (pH 10) afforded the title compound.LCMS calc. for C₂₀H₁₉N₄O₄ (M+H)⁺: m/z=379.1; found: 379.2.

Example 2557-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine-2(1H)-thione

7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one(50 mg, 0.1 mmol) from Example 13 was stirred in 1,4-dioxane (2 mL) and2,4-bis(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiadiphosphetane[Aldrich #: 227439] (58 mg, 0.14 mmol) was added. The mixture was heatedto 100° C. for 3 h and concentrated. Purification by preparative LCMS(pH 10) afforded the title compound. LCMS calc. for C₁₉H₁₇N₄O₂S (M+H)⁺:m/z=365.1; found: 365.1.

Examples 256-269B

The experimental procedures used to prepare the compounds of Examples256 to 269B are summarized in Table 9 below.

TABLE 9

Ex. No. Name R⁷ Procedure* 256 7-(3,5-dimethylisoxazol-4-yl)-9-(1H-pyrazol-4-yl)-4-pyridin- 2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one

 43 257 7-(3,5-dimethylisoxazol-4-yl)- 9-(3-methyl-1H-pyrazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[1,5,4- de][1,4]benzoxazin-2(1H)-one

 43 258 7-(3,5-dimethylisoxazol-4-yl)- 9-(3,5-dimethyl-1H-pyrazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one

 43 259 (4S)-7-(3,5-dimethylisoxazol-4- yl)-9-(6-hydroxypyridin-3-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[1,5,4- de][1,4]benzoxazin-2(1H)-one

 43 260 (4S)-7-(3,5-dimethylisoxazol-4- yl)-9-(2-hydroxypyridin-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[1,5,4- de][1,4]benzoxazin-2(1H)-one

 43 261 (4S)-7-(3,5-dimethylisoxazol-4- yl)-9-(2-hydroxypyridin-3-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[1,5,4- de][1,4]benzoxazin-2(1H)-one

 43 262 9-(anilinomethyl)-7-(3,5- dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5- dihydroimidazo[1,5,4- de][1,4]benzoxazin-2(1H)-one

253 263 7-(3,5-dimethylisoxazol-4-yl)- 9-{[(4-methoxybenzyl)amino]methyl}- 4-pyridin-2-yl-4,5- dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one

253 264 7-(3,5-dimethylisoxazol-4-yl)- 9-(1-hydroxy-2-methylpropyl)-4-pyridin-2-yl-4,5- dihydroimidazo[1,5,4- de][1,4]benzoxazin-2(1H)-one

144 265A 7-(3,5-dimethylisoxazol-4-yl)- F 1559-fluoro-4-pyridin-2-yl-4,5- dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one 265B 7-(3,5-dimethylisoxazol-4-yl)- F 1559-fluoro-4-pyridin-2-yl-4,5- dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one 266A 9-chloro-7-(3,5- Cl  36dimethylisoxazol-4-yl)-4- pyridin-2-yl-4,5- dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one 266B 9-chloro-7-(3,5- Cl  36dimethylisoxazol-4-yl)-4- pyridin-2-yl-4,5- dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one 267A 9-bromo-7-(3,5- Br  36dimethylisoxazol-4-yl)-4- pyridin-2-yl-4,5- dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one 267B 9-bromo-7-(3,5- Br  36dimethylisoxazol-4-yl)-4- pyridin-2-yl-4,5- dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one 268 7-(3,5-dimethylisoxazol-4-yl)- Me  379-methyl-4-pyridin-2-yl-4,5- dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one 269A 7-(3,5-dimethylisoxazol-4-yl)- CN  422-oxo-4-pyridin-2-yl-1,2,4,5- tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-9- carbonitrile 269B 7-(3,5-dimethylisoxazol-4-yl)-CN  42 2-oxo-4-pyridin-2-yl-1,2,4,5- tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-9- carbonitrile *The number in this column indicatesthe Example number of the procedure used to prepare the compound.Analytical Data

¹H NMR data (Varian Inova 500 spectrometer, a Mercury 400 spectrometer,or a Varian (or Mercury) 300 spectrometer) and LCMS mass spectral data(MS) for the compounds of Examples 47A-51, 75-87, 104-108, 110-119,134-136, and 139-143 are provided below in Table 10.

TABLE 10 Example MS No. [M + H]⁺ ¹H NMR Spectrum  47A 419.1  47B 419.1 48A 435.1  48B 435.1  49 366.1 ¹H NMR (300 MHz, DMSO-d6) δ 10.95 (s,1H), 7.22-7.05 (m, 4H), 6.80 (d, J = 8.0 Hz, 1H), 6.71 (d, J = 8.0 Hz,1H), 5.43 (s, 1H), 4.50 (dd, J = 11.6, 2.4 Hz, 1H), 4.33 (dd, J = 11.6,3.0 Hz, 1H), 2.20 (s, 3H), 2.03 (s, 3H).  50 465.1 ¹H NMR (500 MHz,DMSO) δ 10.91 (s, 1H), 8.51 (d, J = 4.6 Hz, 1H), 7.78 (td, J = 7.7, 1.7Hz, 1H), 7.32 (dd, J = 7.2, 5.0 Hz, 1H), 7.19 (d, J = 7.8 Hz, 1H), 6.82(d, J = 8.0 Hz, 1H), 6.73 (d, J = 8.0 Hz, 1H), 5.16 (d, J = 3.9 Hz, 1H),4.90-4.72 (m, 1H), 2.24 (s, 3H), 2.07 (s, 3H), 1.29 (d, J = 6.5 Hz, 3H). 51 449.1  75 363.1 ¹H NMR (400 MHz, dmso) δ 10.98 (s, 1H), 8.47 (s,1H), 7.79 (s, 1H), 7.55 (s, 1H), 7.41 (s, 1H), 7.33 (s, 1H), 7.22 (s,1H), 6.78 (s, 1H), 6.72 (s, 1H), 5.73 (m, 1H), 5.40-5.34 (m, 1H), 2.19(s, 3H), 2.01 (s, 3H).  76 406.1 ¹H NMR (400 MHz, dmso) δ 11.04 (s, 1H),8.54 (d, J = 2.7 Hz, 1H), 8.32 (s, 1H), 7.64 (s, 1H), 6.87 (d, J = 8.0Hz, 1H), 6.77 (d, J = 8.0 Hz, 1H), 5.59 (s, 1H), 4.62 (dd, J = 11.7, 3.4Hz, 1H), 4.52-4.39 (m, 1H), 2.26 (s, 3H), 2.09 (s, 3H)  77 392.1 ¹H NMR(400 MHz, dmso) δ 10.78 (s, 1H), 6.76 (d, J = 8.0 Hz, 1H), 6.65 (d, J =8.0 Hz, 1H), 4.75 (d, 1H), 4.64 (d, 1H), 4.06-4.00 (m, 1H), 3.97-3.90(m, 1H), 3.67-3.49 (m, 2H), 2.62 (s, 3H), 2.28 (s, 3H), 2.11 (s, 3H),1.98-1.88 (m, 1H), 1.7-1.58 (m 4H), 1.37 (s, 1H).  78 367.0 ¹H NMR (500MHz, DMSO) δ 10.91 (s, 1H), 8.51 (d, J = 4.6 Hz, 1H), 7.78 (td, J = 7.7,1.7 Hz, 1H), 7.32 (dd, J = 7.2, 5.0 Hz, 1H), 7.19 (d, J = 7.8 Hz, 1H),6.82 (d, J = 8.0 Hz, 1H), 6.73 (d, J = 8.0 Hz, 1H), 5.16 (d, J = 3.9 Hz,1H), 4.90-4.72 (m, 1H), 2.24 (s, 3H), 2.07 (s, 3H), 1.29 (d, J = 6.5 Hz,3H).  79 433.1 ¹H NMR (400 MHz, dmso) δ 10.61 (s, 1H), 6.74 (d, J = 8.0Hz, 1H), 6.61 (d, J = 7.9 Hz, 1H), 5.30 (bs, 1H), 4.74-4.59 (m, 2H),4.43- 4.32 (m, 1H), 3.99 (d, J = 9.9 Hz, 1H), 3.80-3.66 (m, 1H), 3.44-3.26 (m, 2H), 2.29 (s, 3H), 2.12 (s, 3H), 1.94-1.86 (m, 1H), 1.69- 1.39(m, 4H), 1.32-1.17 (m, 1H), 0.83 (d, J = 6.5 Hz, 3H), 0.74 (d, J = 6.3Hz, 3H).  80 440.2 ¹H NMR (400 MHz, dmso) δ 11.01 (s, 1H), 8.46 (d, J =4.0 Hz, 1H), 8.19 (s, 1H), 7.90 (s, 1H), 7.73 (td, J = 7.7, 1.7 Hz, 1H),7.27 (dd, J = 6.7, 4.8 Hz, 1H), 7.10 (d, J = 7.9 Hz, 1H), 6.98 (s, 1H),5.50 (s, 1H), 4.71 (dd, J = 11.4, 1.9 Hz, 1H), 4.39 (dd, J = 11.4, 3.0Hz, 1H), 3.81 (s, 3H), 2.19 (s, 3H), 2.02 (s, 3H).  81 429.1 ¹H NMR (400MHz, dmso) δ 11.45 (s, 1H), 8.86-8.78 (m, 1H), 8.56- 8.48 (m, 1H), 8.12(dd, J = 8.1, 2.3 Hz, 1H), 7.80 (td, J = 7.7, 1.8 Hz, 1H), 7.63 (dd, J =8.1, 0.7 Hz, 1H), 7.33 (dd, J = 6.6, 4.8 Hz, 1H), 7.21 (d, J = 8.0 Hz,1H), 7.06 (s, 1H), 5.59 (s, 1H), 4.82 (dd, J = 11.5, 1.9 Hz, 1H),4.57-4.44 (m, 1H), 3.02 (s, 6H), 2.26 (s, 3H), 2.09 (s, 3H).  82 497.2 83 530.1 ¹H NMR (400 MHz, dmso) δ 11.52 (s, 1H), 9.18 (s, 1H), 9.05 (s,2H), 8.57-8.45 (m, 1H), 7.80 (td, J = 7.7, 1.8 Hz, 1H), 7.33 (dd, J =7.0, 5.3 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.10 (s, 1H), 5.60 (s, 1H),4.82 (dd, J = 11.5, 2.0 Hz, 1H), 4.55-4.44 (m, 1H), 2.26 (s, 3H), 2.09(s, 3H).  84 427.1 ¹H NMR (400 MHz, dmso) δ 10.61 (s, 1H), 6.74 (d, J =8.0 Hz, 1H), 6.61 (d, J = 7.9 Hz, 1H), 5.30 (bs, 1H), 4.74-4.59 (m, 2H),4.43- 4.32 (m, 1H), 3.99 (d, J = 9.9 Hz, 1H), 3.80-3.66 (m, 1H), 3.44-3.26 (m, 2H), 2.29 (s, 3H), 2.12 (s, 3H), 1.94-1.86 (m, 1H), 1.69- 1.39(m, 4H), 1.32-1.17 (m, 1H), 0.83 (d, J = 6.5 Hz, 3H), 0.74 (d, J = 6.3Hz, 3H).  85 429.1 ¹H NMR (400 MHz, dmso) δ 11.17 (s, 3H), 8.58-8.46 (m,1H), 7.80 (td, J = 7.7, 1.8 Hz, 1H), 7.51 (d, J = 1.9 Hz, 1H), 7.38-7.28(m, 1H), 7.22 (d, J = 8.0 Hz, 1H), 6.87 (s, 1H), 6.44 (d, J = 1.9 Hz,1H), 5.57 (s, 1H), 4.81 (dd, J = 11.5, 2.0 Hz, 1H), 4.50 (dd, J = 11.5,3.2 Hz, 1H), 3.83 (s, 3H), 2.25 (s, 3H), 2.08 (s, 3H).  86 447.1 ¹H NMR(400 MHz, dmso) δ 11.62 (s, 1H), 8.48 (d, 1H), 7.86 (d, J = 16.1 Hz,1H), 7.78 (td, J = 7.7, 1.8 Hz, 1H), 7.36-7.27 (m, 2H), 7.20 (d, J = 7.9Hz, 1H), 6.66 (d, J = 16.1 Hz, 1H), 5.56 (s, 1H), 4.79 (dd, J = 11.5,2.0 Hz, 1H), 4.55-4.44 (m, 1H), 2.23 (s, 3H), 2.06 (s, 3H).  87 430.1 ¹HNMR (400 MHz, dmso) δ 11.19 (s, 1H), 8.85 (bs, 1H), 8.53-8.44 (m, 1H),7.79 (td, J = 7.7, 1.8 Hz, 1H), 7.32 (dd, J = 7.2, 5.3 Hz, 1H), 7.18 (d,J = 8.0 Hz, 1H), 6.80 (s, 1H), 6.02 (s, 1H), 5.55 (s, 1H), 4.77 (dd, J =11.5, 2.0 Hz, 1H), 4.44 (dd, J = 11.5, 3.1 Hz, 1H), 3.81- 3.70 (m, 2H),3.37-3.25 (m, 2H), 2.78-2.60 (m, 2H), 2.22 (s, 3H), 2.05 (s, 3H). 104414.2 105 400.2 1H NMR (400 MHz, CD₃OD) δ 8.56 (ddd, J = 4.9, 1.7, 0.9Hz, 1H), 7.69 (ddd, J = 7.8, 1.8 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.31(ddd, J = 7.6, 4.9, 0.9 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 6.62 (d, J =8.0 Hz, 1H), 6.38 (t, J = 2.1 Hz, 1H), 6.19-6.07 (m, 1H), 4.91 (dd, J =11.6, 1.4 Hz, 1H), 4.61 (dd, J = 11.6, 3.1 Hz, 1H), 4.32-4.22 (m, 1H),4.21-4.11 (m, 1H), 3.89 (m, 1H), 3.84-3.73 (m, 1H), 2.26 (s, 3H), 2.12(s, 3H). 106A 402.2 1H NMR (400 MHz, CD₃OD) δ 8.54 (d, J = 4.1 Hz, 1H),7.83-7.67 (m, 1H), 7.41-7.28 (m, 2H), 7.07 (d, J = 8.3 Hz, 1H), 6.82 (d,J = 7.9 Hz, 1H), 5.99 (s, 1H), 4.95-4.90 (m, 1H), 4.61 (dd, J = 11.7,3.1 Hz, 2H), 3.51-3.37 (m, 1H), 3.15 (d, J = 8.6 Hz, 1H), 3.01-2.77 (m,3H), 2.32 (d, J = 8.6 Hz, 1H), 2.27 (s, 3H), 2.25-2.14 (m, 1H), 2.13 (s,3H). 106B 402.2 1H NMR (400 MHz, CD₃OD) δ 8.57 (s, 1H), 7.76 (s, 1H),7.36 (d, J = 8.3 Hz, 2H), 7.10 (d, J = 8.3 Hz, 1H), 6.85-6.75 (m, 1H),6.00 (s, 1H), 4.94 (s, 2H), 4.71-4.58 (m, 1H), 3.45 (s, 1H), 3.35 (s,1H), 3.13 (s, 1H), 2.83 (s, 1H), 2.29 (s, 3H), 2.15 (s, 3H), 1.89 (s,2H). 107 414.2 ¹H NMR (400 MHz, CD₃OD) δ 8.59 (d, J = 4.1 Hz, 1H),7.78-7.68 (m, 1H), 7.44 (dd, J = 8.4, 1.6 Hz, 1H), 7.35 (dd, J = 6.9,5.5 Hz, 1H), 7.17 (dd, J = 8.4, 4.6 Hz, 1H), 6.71 (dd, J = 14.3, 8.0 Hz,1H), 6.36 (s, 1H), 6.19 (d, J = 9.1 Hz, 1H), 4.96 (d, J = 11.7 Hz, 2H),4.87- 4.82 (m, 1H), 4.78 (d, J = 14.4 Hz, 1H), 4.68 (dd, J = 11.7, 2.7Hz, 3H), 4.60-4.23 (m, 2H), 2.29 (d, J = 2.4 Hz, 3H), 2.19-2.11 (m, 3H).108 416.2 110 456.2 111 484.2 112 494.2 113A 444.2 113B 444.2 114A 470.2114B 470.2 115 480.2 116 456.2 1H NMR (400 MHz, CD₃OD) δ 8.58 (d, J =4.2 Hz, 0H), 7.74 (td, J = 7.8, 1.7 Hz, 1H), 7.46-7.30 (m, 2H), 7.12 (d,J = 8.4 Hz, 1H), 6.71 (d, J = 7.9 Hz, 1H), 6.31 (m, 1H), 6.09 (m, 1H),4.84 (dd, J = 11.6, 2.5 Hz, 1H), 4.61 (dd, J = 11.6, 3.0 Hz, 1H),3.85-3.67 (m, 2H), 2.96-2.72 (m, 2H), 2.28 (s, 3H), 2.26-2.18 (m, 1H),2.13 (s, 3H), 2.10 (s, 1H). 117 458.2 1H NMR (400 MHz, CD₃OD) δ 8.57 (d,J = 4.0 Hz, 1H), 7.82-7.67 (m, 1H), 7.36 (d, J = 8.3 Hz, 2H), 7.09 (d, J= 8.3 Hz, 1H), 6.77 (d, J = 8.0 Hz, 1H), 6.01 (s, 1H), 4.93 (d, J = 11.8Hz, 2H), 4.68-4.57 (m, 1H), 3.55-3.42 (m, 1H), 3.26 (d, J = 1.6 Hz, 2H),2.98 (s, 3H), 2.65 (s, 1H), 2.28 (d, J = 1.7 Hz, 3H), 2.14 (d, J = 1.7Hz, 6H), 1.66 (d, J = 11.6 Hz, 1H), 1.24 (s, 1H). 118 484.2 119 494.2134 432.2 (400 MHz, DMSO-d₆) δ 8.96 (d, J = 4.9 Hz, 1H), 8.56 (dd, J =4.6, 1.5 Hz, 1H), 7.49 (dd, J = 8.0, 4.7 Hz, 1H), 7.12 (dd, J = 8.0, 1.4Hz, 1H), 6.88 (d, J = 8.0 Hz, 1H), 6.80 (d, J = 8.0 Hz, 1H), 6.41 (dd, J= 2.5, 2.5 Hz, 1H), 4.65-4.43 (m, 2H), 3.01-2.82 (m, 1H), 2.24 (s, 3H),2.08 (s, 3H), 0.70 (dd, J = 9.0, 2.7 Hz, 4H). 135 436.2 (400 MHz,DMSO-d₆) δ 8.93 (t, J = 5.9 Hz, 1H), 8.59 (dd, J = 4.6, 1.5 Hz, 1H),7.51 (dd, J = 8.0, 4.6 Hz, 1H), 7.11 (dd, J = 8.0, 1.4 Hz, 1H), 6.87 (d,J = 8.0 Hz, 1H), 6.80 (d, J = 8.0 Hz, 1H), 6.59-6.49 (m, 1H), 4.65-4.44(m, 2H), 3.55 (t, J = 6.0 Hz, 2H), 3.45-3.35 (m, 2H), 2.24 (s, 3H), 2.07(s, 3H). 136 474.1 (400 MHz, DMSO-d₆) δ 11.10 (s, 1H), 9.58 (t, J = 6.6Hz, 1H), 8.64 (dd, J = 4.6, 1.4 Hz, 1H), 7.57 (dd, J = 8.1, 4.6 Hz, 1H),7.18 (dd, J = 8.0, 1.3 Hz, 1H), 6.89 (d, J = 8.0 Hz, 1H), 6.81 (d, J =8.0 Hz, 1H), 6.54-6.29 (m, 1H), 4.60-4.46 (m, 2H), 4.21-4.03 (m, 2H),2.24 (s, 3H), 2.07 (s, 3H). 139 496.0 (500 MHz, DMSO-d₆) δ 10.97 (s,1H), 8.56-8.46 (m, 2H), 7.78 (ddd, J = 7.7, 7.7, 1.8 Hz, 1H), 7.31 (dd,J = 6.7, 4.9 Hz, 1H), 7.29- 7.16 (m, 5H), 7.12 (d, J = 7.9 Hz, 1H), 6.60(s, 1H), 5.52 (t, J = 2.4 Hz, 1H), 4.75 (dd, J = 11.5, 2.0 Hz, 1H), 4.40(dd, J = 11.5, 3.1 Hz, 1H), 4.34 (d, J = 5.8 Hz, 2H), 3.48 (s, 2H), 2.15(s, 3H), 1.99 (s, 3H). 140 450.0 (500 MHz, DMSO-d₆) δ 10.94 (s, 1H),8.52 (d, J = 4.2 Hz, 1H), 8.34 (dd, J = 6.2, 6.2 Hz, 1H), 7.78 (ddd, J =7.7, 7.7, 1.8 Hz, 1H), 7.32 (dd, J = 6.9, 4.9 Hz, 1H), 7.15 (d, J = 7.9Hz, 1H), 6.70 (s, 1H), 5.52 (s, 1H), 4.75 (dd, J = 11.4, 2.0 Hz, 1H),4.41 (dd, J = 11.5, 3.1 Hz, 1H), 4.36 (d, J = 6.2 Hz, 2H), 3.85 (s, 2H),3.32 (s, 3H), 2.22 (s, 3H), 2.05 (s, 3H). 141 456.1 (500 MHz, DMSO-d₆) δ11.04 (s, 1H), 8.51 (d, J = 4.1 Hz, 1H), 7.78 (ddd, J = 7.7, 7.7, 1.8Hz, 1H), 7.42 (dd, J = 6.1, 6.1 Hz, 1H), 7.32 (dd, J = 6.7, 4.9 Hz, 1H),7.14 (d, J = 7.9 Hz, 1H), 6.84 (s, 1H), 5.54 (t, J = 2.4 Hz, 1H), 4.77(dd, J = 11.5, 2.0 Hz, 1H), 4.43 (dd, J = 11.5, 3.1 Hz, 1H), 4.27 (d, J= 6.0 Hz, 2H), 2.88 (s, 3H), 2.23 (s, 3H), 2.05 (s, 3H). 142 463.2 (500MHz, DMSO-d₆) δ 10.88 (s, 1H), 8.52 (d, J = 4.1 Hz, 1H), 7.78 (ddd, J =7.7, 7.7, 1.7 Hz, 1H), 7.31 (dd, J = 6.9, 4.9 Hz, 1H), 7.13 (d, J = 7.9Hz, 1H), 6.70 (s, 1H), 6.35-6.13 (m, 1H), 6.04-5.78 (m, 1H), 5.52 (s,1H), 4.75 (dd, J = 11.4, 2.0 Hz, 1H), 4.41 (dd, J = 11.4, 3.1 Hz, 1H),4.25 (s, 2H), 3.87-3.52 (m, 1H), 2.22 (s, 3H), 2.05 (s, 3H), 1.02 (d, J= 6.5 Hz, 6H). 143 463.1 (500 MHz, DMSO-d₆) δ 11.08 (s, 1H), 9.71 (br s,1H), 8.94 (t, J = 5.5 Hz, 1H), 8.50 (d, J = 4.2 Hz, 1H), 7.79 (ddd, J =7.7, 7.7, 1.7 Hz, 1H), 7.32 (dd, J = 6.9, 4.9 Hz, 1H), 7.16 (d, J = 7.9Hz, 1H), 6.73 (s, 1H), 5.55 (s, 1H), 4.78 (dd, J = 11.5, 2.0 Hz, 1H),4.49-4.36 (m, 3H), 3.97 (s, 2H), 2.81 (s, 6H), 2.22 (s, 3H), 2.05 (s,3H). 161 418.0 162 402.0 163 431.0 164 388.2 ¹H NMR (500 MHz, CD₃OD) δ8.48 (d, J = 4.7 Hz, 1H), 7.95-7.73 (m, 1H), 7.40 (d, J = 7.9 Hz, 1H),7.37 (dd, J = 7.6, 4.9 Hz, 1H), 7.21 (d, J = 8.3 Hz, 1H), 7.17 (d, J =8.3 Hz, 1H), 5.85 (t, 1H), 5.02 (dd, J = 12.0, 1.8 Hz, 1H), 4.64 (dd, J= 11.9, 2.9 Hz, 1H), 4.29 (p, J = 6.2 Hz, 2H), 3.61 (q, J = 5.1 Hz, 2H),2.36-2.28 (m, 2H), 2.23 (s, 3H), 2.08 (s, 3H). 165 404.2 ¹H NMR (500MHz, CD₃OD) δ 8.49 (d, J = 4.9 Hz, 1H), 7.88 (td, J = 7.8, 1.7 Hz, 1H),7.43 (d, J = 7.9 Hz, 1H), 7.38 (dd, J = 6.8, 5.0 Hz, 1H), 7.14 (d, J =8.2 Hz, 1H), 7.11 (d, J = 8.2 Hz, 1H), 6.01 (t, 1H), 4.98 (dd, J = 12.1,1.8 Hz, 1H), 4.66 (dd, J = 12.1, 2.9 Hz, 1H), 4.33 (dd, J = 8.9, 3.1 Hz,2H), 3.46-3.41 (m, 2H), 2.81 (s, 1H), 2.24 (s, 3H), 2.08 (s, 3H). 166445.2 ¹H NMR (500 MHz, DMSO) δ 8.55-8.49 (m, 1H), 7.75 (td, J = 7.7, 1.8Hz, 1H), 7.32 (dd, J = 6.8, 4.9 Hz, 1H), 7.09 (d, J = 8.1 Hz, 1H), 6.89(d, J = 8.1 Hz, 1H), 6.84 (d, J = 7.9 Hz, 1H), 6.07 (t, J = 2.5 Hz, 1H),4.75 (dd, J = 11.6, 2.3 Hz, 1H), 4.56 (dd, J = 11.6, 3.0 Hz, 1H), 4.03-3.90 (m, 2H), 3.62 (t, J = 5.5 Hz, 2H), 3.31 (d, J = 5.3 Hz, 1H), 3.21(dt, J = 12.0, 5.5 Hz, 1H), 2.80 (s, 3H), 2.21 (s, 3H), 2.04 (s, 3H).167 489.2 168A 418.2 ¹H NMR (300 MHz, CD₃OD) δ 8.49-8.44 (m, 1H), 7.87(td, J = 7.8, 1.8 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.37 (dd, J = 7.1,5.3 Hz, 1H), 7.14 (s, 2H), 6.35 (t, 1H), 5.07 (dd, J = 12.1, 1.5 Hz,1H), 4.67 (dd, J = 12.1, 2.6 Hz, 1H), 4.55 (d, J = 3.8 Hz, 2H), 3.99(dd, J = 10.5, 4.5 Hz, 2H), 3.75 (td, J = 9.2, 3.4 Hz, 1H), 3.53 (d, J =10.4 Hz, 1H), 2.22 (s, 3H), 2.11 (dd, J = 7.5, 3.8 Hz, 2H), 2.06 (s,3H). 168B 418.2 ¹H NMR (500 MHz, DMSO) δ 8.56-8.51 (m, 1H), 7.71 (td, J= 7.8, 1.8 Hz, 1H), 7.32-7.26 (m, 1H), 6.95 (d, J = 8.1 Hz, 1H), 6.80(d, J = 8.1 Hz, 1H), 6.60 (d, J = 7.9 Hz, 1H), 6.10 (t, 1H), 4.94 (s,1H), 4.81 (dd, J = 11.4, 1.3 Hz, 1H), 4.53 (dd, J = 11.5, 2.8 Hz, 1H),4.29 (s, 1H), 3.71 (tt, J = 8.7, 4.1 Hz, 1H), 3.52 (d, J = 10.3 Hz, 1H),3.49- 3.43 (m, 2H), 2.19 (s, 3H), 2.02 (s, 3H), 1.90 (dtd, J = 13.1,8.8, 4.6 Hz, 1H), 1.82-1.75 (m, 1H). 169 432.2 ¹H NMR (500 MHz, DMSO) δ8.55 (d, J = 4.0 Hz, 1H), 7.76 (td, J = 7.7, 1.8 Hz, 1H), 7.35-7.30 (m,1H), 7.04 (d, J = 8.1 Hz, 1H), 6.85 (d, J = 8.1 Hz, 1H), 6.80 (d, J =7.9 Hz, 1H), 5.96 (t, J = 2.8 Hz, 1H), 4.65 (dd, J = 11.5, 2.8 Hz, 1H),4.62 (d, J = 4.1 Hz, 1H), 4.54 (dd, J = 11.5, 3.1 Hz, 1H), 3.62 (td, J =8.6, 4.5 Hz, 2H), 3.57 (dt, J = 8.6, 4.3 Hz, 1H), 3.03 (ddd, J = 12.9,9.9, 3.0 Hz, 2H), 2.21 (s, 3H), 2.05 (s, 3H), 1.65-1.55 (m, 2H), 1.31(ddt, J = 13.0, 9.1, 4.8 Hz, 1H), 1.19-1.09 (m, 1H). 170A 432.2 170B432.2 171 459.2 172 431.2 ¹H NMR (300 MHz, CD₃OD) δ 8.57 (d, J = 4.9 Hz,1H), 7.75 (td, J = 7.8, 1.8 Hz, 1H), 7.35 (dd, J = 7.6, 4.9 Hz, 1H),7.18 (d, J = 8.2 Hz, 1H), 6.98 (d, J = 8.2 Hz, 1H), 6.83 (d, J = 7.9 Hz,1H), 5.95 (t, J = 2.9 Hz, 1H), 4.76 (dd, J = 11.6, 2.8 Hz, 1H), 4.60(dd, J = 11.6, 3.1 Hz, 1H), 4.06 (d, J = 1.5 Hz, 2H), 3.69-3.51 (m, 2H),3.25- 3.15 (m, 2H), 2.26 (s, 3H), 2.11 (s, 3H). 173 495.2 ¹H NMR (500MHz, DMSO) δ 8.58-8.51 (m, 1H), 7.76 (td, J = 7.7, 1.8 Hz, 1H), 7.33(ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 7.09 (d, J = 8.1 Hz, 1H), 6.89 (d, J =8.2 Hz, 1H), 6.85 (d, J = 7.9 Hz, 1H), 6.02 (t, J = 2.8 Hz, 1H), 4.74(dd, J = 11.5, 2.8 Hz, 1H), 4.58 (dd, J = 11.5, 3.0 Hz, 1H), 3.44 (pt, J= 6.3, 3.1 Hz, 4H), 3.12-2.99 (m, 4H), 2.84 (s, 3H), 2.21 (s, 3H), 2.04(s, 3H). 174 459.2 175 441.2 176 446.2 177 461.2 ¹H NMR (500 MHz, DMSO)δ 8.54 (d, J = 4.6 Hz, 1H), 7.76 (td, J = 7.7, 1.6 Hz, 1H), 7.33 (dd, J= 7.5, 4.9 Hz, 1H), 7.06 (d, J = 8.1 Hz, 1H), 6.86 (d, J = 8.1 Hz, 1H),6.81 (d, J = 7.9 Hz, 1H), 5.99 (t, J = 2.6 Hz, 1H), 4.68 (dd, J = 11.5,2.7 Hz, 1H), 4.55 (dd, J = 11.5, 3.0 Hz, 1H), 4.35 (t, J = 5.0 Hz, 1H),3.45 (q, J = 5.8 Hz, 2H), 3.31 (dd, J = 6.2, 3.2 Hz, 4H), 2.40-2.33 (m,4H), 2.33- 2.26 (m, 2H), 2.21 (s, 3H), 2.04 (s, 3H). 178 493.2 179 507.2180A 445.2 180B 445.2 ¹H NMR (500 MHz, DMSO) δ 8.55 (ddd, J = 4.8, 1.6,0.8 Hz, 1H), 7.77 (td, J = 7.7, 1.8 Hz, 1H), 7.33 (ddd, J = 7.5, 4.8,0.9 Hz, 1H), 7.08 (d, J = 8.1 Hz, 1H), 6.89 (d, J = 5.1 Hz, 1H), 6.87(d, J = 4.9 Hz, 1H), 6.02 (t, J = 2.9 Hz, 1H), 4.70 (dd, J = 11.5, 3.0Hz, 1H), 4.57 (dd, J = 11.5, 3.1 Hz, 1H), 3.44 (d, J = 12.2 Hz, 4H),3.35 (d, J = 10.6 Hz, 4H), 2.29 (q, J = 7.4 Hz, 3H), 2.22 (s, 3H), 2.05(s, 3H), 0.95 (t, J = 7.4 Hz, 2H). 181A 431.2 ¹H NMR (500 MHz, DMSO) δ8.99 (s, 1H), 8.47 (d, J = 4.3 Hz, 1H), 7.92-7.79 (m, 1H), 7.36 (dd, J =7.2, 5.2 Hz, 1H), 7.28 (s, 1H), 7.12 (d, J = 8.2 Hz, 1H), 7.06 (d, J =8.1 Hz, 1H), 6.35 (t, 1H), 5.05 (d, J = 11.9 Hz, 1H), 4.59 (dd, J =12.0, 2.5 Hz, 1H), 4.17-4.08 (m, 1H), 3.99 (d, J = 7.7 Hz, 1H), 3.91 (s,1H), 3.69 (dd, J = 11.1, 4.5 Hz, 1H), 3.54 (d, J = 6.3 Hz, 1H), 2.56 (s,3H), 2.36 (dt, J = 13.5, 6.9 Hz, 1H), 2.20 (s, 3H), 2.16 (d, J = 6.2 Hz,1H), 2.02 (s, 3H). 181B 431.2 ¹H NMR (500 MHz, DMSO) δ 8.94 (d, J = 44.9Hz, 1H), 8.46 (d, J = 4.5 Hz, 1H), 7.85 (td, J = 7.8, 1.6 Hz, 1H), 7.36(dd, J = 7.1, 5.2 Hz, 1H), 7.29 (s, 1H), 7.13 (d, J = 8.2 Hz, 1H), 7.08(d, J = 8.2 Hz, 1H), 6.40 (t, 1H), 5.05 (d, J = 11.5 Hz, 1H), 4.61 (dd,J = 12.0, 2.4 Hz, 1H), 4.01 (d, J = 10.0 Hz, 1H), 3.91 (s, 1H), 3.89 (d,J = 5.2 Hz, 1H), 3.79 (dd, J = 11.3, 6.5 Hz, 1H), 3.72-3.66 (m, 1H),2.62 (s, 3H), 2.35 (dq, J = 14.8, 8.1, 7.3 Hz, 2H), 2.20 (s, 3H), 2.02(s, 3H). 182A 517.3 182B 517.3 183 471.4 184 475.2 185 406.2 ¹H NMR (500MHz, CD₃OD) δ 8.61-8.53 (m, 1H), 7.69 (td, J = 7.8, 1.8 Hz, 1H), 7.31(dd, J = 6.9, 4.9 Hz, 1H), 7.06 (d, J = 8.1 Hz, 1H), 6.89 (d, J = 8.1Hz, 1H), 6.59 (d, J = 7.9 Hz, 1H), 6.08 (tff, 1H), 4.85 (d, J = 1.8 Hz,1H), 4.54 (dd, J = 11.5, 2.8 Hz, 1H), 3.75 (ddd, J = 11.7, 7.1, 4.8 Hz,1H), 3.71-3.65 (m, 1H), 3.60 (ddd, J = 14.7, 7.0, 4.7 Hz, 1H), 3.51-3.42(m, 1H), 3.15 (s, 3H), 2.81 (s, 1H), 2.22 (s, 3H), 2.07 (s, 3H). 186362.2 ¹H NMR (500 MHz, CD₃OD) δ 8.59 (d, J = 4.9 Hz, 1H), 7.70 (td, J =7.8, 1.7 Hz, 1H), 7.31 (dd, J = 6.9, 5.0 Hz, 1H), 7.05 (d, J = 8.1 Hz,1H), 6.85 (d, J = 8.1 Hz, 1H), 6.62 (d, J = 7.9 Hz, 1H), 5.66 (t, 1H),4.91 (dd, J = 11.4, 1.6 Hz, 1H), 4.48 (dd, J = 11.4, 3.0 Hz, 1H), 3.00(s, 3H), 2.24 (s, 3H), 2.09 (s, 3H). 187 376.2 ¹H NMR (500 MHz, CD₃OD) δ8.57 (ddd, J = 4.9, 1.6, 0.9 Hz, 1H), 7.69 (td, J = 7.8, 1.8 Hz, 1H),7.31 (ddd, J = 7.6, 4.9, 0.8 Hz, 1H), 7.07 (d, J = 8.1 Hz, 1H), 6.90 (d,J = 8.1 Hz, 1H), 6.58 (d, J = 8.0 Hz, 1H), 6.01 (t, J = 2.2 Hz, 1H),4.82 (dd, J = 1.9 Hz, 1H), 4.56 (dd, J = 11.5, 2.9 Hz, 1H), 3.08 (s,6H), 2.22 (s, 3H), 2.07 (s, 3H). 188 459.2 ¹H NMR (300 MHz, CD₃OD) δ8.54 (d, J = 4.1 Hz, 1H), 7.85-7.76 (m, 1H), 7.37 (dd, J = 7.1, 5.4 Hz,1H), 7.16 (d, J = 8.2 Hz, 1H), 7.09 (d, J = 7.8 Hz, 1H), 7.05 (d, J =8.2 Hz, 1H), 6.03 (t, 1H), 4.80 (d, J = 11.5 Hz, 2H), 4.69- 4.59 (m,2H), 3.95 (d, J = 13.4 Hz, 2H), 3.88-3.82 (m, 1H), 3.23-3.05 (m, 2H),2.25 (s, 3H), 2.10 (s, 3H), 1.77 (d, J = 20.7 Hz, 2H), 1.47 (d, J = 12.0Hz, 2H). 189 473.2 190 473.2 ¹H NMR (500 MHz, DMSO) δ 8.54 (d, J = 4.2Hz, 1H), 7.80-7.68 (m, 1H), 7.32 (dd, J = 6.9, 4.9 Hz, 1H), 7.05 (d, J =8.1 Hz, 1H), 6.86 (d, J = 8.1 Hz, 1H), 6.79 (d, J = 7.9 Hz, 1H), 5.97(t, J = 2.6 Hz, 1H), 4.68 (dd, J = 11.5, 2.6 Hz, 1H), 4.54 (dd, J =11.5, 3.0 Hz, 1H), 3.79-3.71 (m, 2H), 3.71-3.61 (m, 1H), 2.99 (t, J =11.4 Hz, 2H), 2.21 (s, 3H), 2.05 (s, 3H), 1.75 (s, 3H), 1.62 (dd, J =34.6, 10.1 Hz, 2H), 1.39-1.27 (m, 1H), 1.21-1.09 (m, 1H). 191 474.2 192445.2 193A 457.2 193B 457.2 194 446.2 195 445.2 196 503.2 197 531.2 198392.2 199 491.3 200 391.2 201A 459.2 201B 459.2 202A 417.3 202B 417.3203 513.3 205 489.4 ¹H NMR (300 MHz, CD₃OD) δ 8.58 (d, J = 4.0 Hz, 1H),7.69 (t, J = 7.7 Hz, 1H), 7.41-7.23 (m, 1H), 7.05 (d, J = 8.1 Hz, 1H),6.90 (d, J = 8.2 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 6.04 (s, 1H), 4.84(s, 1H), 4.57 (dd, J = 11.5, 2.6 Hz, 1H), 4.53-4.42 (m, 1H), 4.01-3.89(m, 1H), 3.87- 3.76 (m, 3H), 3.58 (q, J = 9.7, 8.5 Hz, 1H), 3.43 (dd, J= 9.8, 5.4 Hz, 1H), 3.34-3.24 (m, 3H), 2.23 (s, 4H), 2.08 (s, 3H),2.04-1.92 (m, 1H). 206 485.4 ¹H NMR (500 MHz, DMSO) δ 8.63-8.44 (m, 4H),8.25 (d, J = 6.9 Hz, 1H), 7.72 (td, J = 7.8, 1.8 Hz, 1H), 7.44- 7.21 (m,1H), 6.96 (d, J = 8.1 Hz, 1H), 6.81 (d, J = 8.1 Hz, 1H), 6.66 (d, J =7.9 Hz, 1H), 6.09 (s, 1H), 4.84 (dd, J = 11.5, 1.3 Hz, 1H), 4.50 (dd, J= 11.5, 2.8 Hz, 1H), 4.28 (h, J = 6.2 Hz, 1H), 3.95-3.67 (m, 2H),3.54-3.38 (m, 1H), 3.24 (dd, J = 9.9, 4.8 Hz, 1H), 2.20 (s, 3H), 2.05(d, J = 19.4 Hz, 4H), 1.79 (dq, J = 13.0, 6.3 Hz, 1H), 1.47 (ddd, J =12.4, 7.6, 4.9 Hz, 1H), 0.61 (tdd, J = 13.1, 6.5, 3.4 Hz, 4H). 207 495.3208 473.2 209 487.2 ¹H NMR (300 MHz, CD₃OD) δ 8.74-8.45 (m, 1H), 7.69(td, J = 7.8, 1.7 Hz, 1H), 7.31 (dd, J = 7.6, 4.9 Hz, 1H), 7.05 (d, J =8.1 Hz, 1H), 6.89 (d, J = 8.1 Hz, 1H), 6.59 (d, J = 7.9 Hz, 1H), 6.04(s, 1H), 4.85 (dd, J = 11.5, 1.3 Hz, 1H), 4.55 (dd, J = 11.5, 2.8 Hz,1H), 4.40 (p, J = 5.8 Hz, 1H), 3.95 (dd, J = 9.8, 6.3 Hz, 1H), 3.89-3.75(m, 1H), 3.60 (td, J = 9.6, 8.8, 6.0 Hz, 1H), 3.45-3.33 (m, 1H), 2.35(dq, J = 14.1, 7.1 Hz, 1H), 2.23 (s, 4H), 2.08 (s, 3H), 1.91 (dq, J =12.8, 5.8 Hz, 1H), 1.02 (dd, J = 19.1, 6.9 Hz, 6H). 210 499.2 211 484.2213 529.2 214 509.2 ¹H NMR (300 MHz, DMSO) δ 8.53 (d, J = 4.0 Hz, 1H),7.72 (td, J = 7.7, 1.8 Hz, 1H), 7.42 (s, 1H), 7.29 (dd, J = 6.8, 4.9 Hz,1H), 6.95 (d, J = 8.1 Hz, 1H), 6.80 (d, J = 8.1 Hz, 1H), 6.63 (d, J =7.9 Hz, 1H), 6.10 (t, 1H), 4.81 (d, J = 10.5 Hz, 1H), 4.49 (d, J = 8.7Hz, 1H), 3.91 (d, J = 5.6 Hz, 2H), 3.81-3.71 (m, 1H), 3.36 (d, J = 9.8Hz, 1H), 3.21 (d, J = 3.4 Hz, 1H), 3.03-2.93 (m, 2H), 2.18 (s, 3H), 2.01(s, 3H), 1.86-1.75 (m, 2H), 1.12 (t, J = 7.3 Hz, 3H). 215 523.2 ¹H NMR(300 MHz, DMSO) δ 8.53 (d, J = 4.0 Hz, 1H), 7.72 (td, J = 7.7, 1.7 Hz,1H), 7.43 (s, 1H), 7.30 (dd, J = 6.7, 4.8 Hz, 1H), 6.95 (d, J = 8.1 Hz,1H), 6.80 (d, J = 8.1 Hz, 1H), 6.63 (d, J = 7.9 Hz, 1H), 6.10 (t, 1H),4.81 (d, J = 10.9 Hz, 1H), 4.50 (d, J = 8.8 Hz, 1H), 3.91 (d, J = 5.8Hz, 2H), 3.81-3.71 (m, 1H), 3.41-3.32 (m, 1H), 3.22 (d, J = 3.2 Hz, 1H),3.02-2.92 (m, 2H), 2.18 (s, 3H), 2.01 (s, 3H), 1.88-1.73 (m, 2H),1.67-1.54 (m, 2H), 0.94 (t, J = 7.5 Hz, 3H). 216 488.2 217 523.2 218521.2 219 489.2 220 509.2 ¹H NMR (300 MHz, CD₃OD) δ 8.58 (d, J = 4.9 Hz,1H), 7.82-7.58 (m, 1H), 7.33 (dd, J = 7.6, 4.9 Hz, 1H), 7.07 (d, J = 8.2Hz, 1H), 6.91 (d, J = 8.2 Hz, 1H), 6.62 (d, J = 7.9 Hz, 1H), 6.06 (s,1H), 4.90 (s, 1H), 4.69-4.49 (m, 2H), 4.00-3.80 (m, 2H), 3.59-3.42 (m,2H), 2.87 (s, 3H), 2.70 (s, 3H), 2.24 (s, 3H), 2.09 (s, 3H), 2.03 (s,2H). 221 503.2 ¹H NMR (300 MHz, CD₃OD) δ 8.58 (d, J = 4.0 Hz, 1H),7.85-7.57 (m, 1H), 7.44-7.21 (m, 1H), 7.07 (d, J = 8.3 Hz, 1H), 6.91 (d,J = 8.2 Hz, 1H), 6.61 (d, J = 8.1 Hz, 1H), 6.05 (s, 1H), 5.14 (s, 1H),4.84 (s, 1H), 4.61 (d, J = 11.9 Hz, 1H), 4.22 (s, 1H), 4.12 (s, 2H),3.98-3.78 (m, 2H), 3.61-3.43 (m, 3H), 3.38 (s, 3H), 2.75 (d, J = 18.9Hz, 3H), 2.24 (s, 3H), 2.09 (s, 3H). 222 473.2 ¹H NMR (300 MHz, CD₃OD) δ8.58 (d, J = 4.9 Hz, 1H), 7.81-7.62 (m, 1H), 7.33 (dd, J = 7.6, 4.9 Hz,1H), 7.07 (dd, J = 8.2, 3.0 Hz, 1H), 6.91 (dd, J = 8.1, 3.0 Hz, 1H),6.61 (d, J = 7.9 Hz, 1H), 6.04 (s, 1H), 5.34-5.05 (m, 1H), 4.84 (s, 1H),4.67-4.51 (m, 1H), 4.02-3.78 (m, 2H), 3.57-3.41 (m, 2H), 2.84 (s, 3H),2.24 (s, 3H), 2.09 (t, J = 6.4 Hz, 6H). 224 459.2 ¹H NMR (500 MHz, DMSO)δ 8.63-8.46 (m, 1H), 7.77 (td, J = 7.7, 1.8 Hz, 1H), 7.40-7.26 (m, 1H),7.08 (d, J = 8.2 Hz, 1H), 6.88 (dd, J = 8.0, 3.8 Hz, 2H), 6.02 (t, J =2.9 Hz, 1H), 4.64 (ddd, J = 65.0, 11.5, 3.0 Hz, 2H), 3.54- 3.14 (m, 8H),2.22 (s, 3H), 2.06 (d, J = 5.8 Hz, 3H), 1.97 (s, 3H). 225 473.2 ¹H NMR(500 MHz, DMSO) δ 8.55 (ddd, J = 4.8, 1.6, 0.8 Hz, 1H), 7.77 (td, J =7.7, 1.8 Hz, 1H), 7.33 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 7.08 (d, J = 8.1Hz, 1H), 6.89 (d, J = 5.1 Hz, 1H), 6.87 (d, J = 4.9 Hz, 1H), 6.02 (t, J= 2.9 Hz, 1H), 4.70 (dd, J = 11.5, 3.0 Hz, 1H), 4.57 (dd, J = 11.5, 3.1Hz, 1H), 3.44 (d, J = 12.2 Hz, 4H), 3.35 (d, J = 10.6 Hz, 4H), 2.29 (q,J = 7.4 Hz, 3H), 2.22 (s, 3H), 2.05 (s, 3H), 0.95 (t, J = 7.4 Hz, 2H).226 509.2 ¹H NMR (300 MHz, dmso) δ 8.53 (d, J = 4.0 Hz, 1H), 7.76 (td, J= 7.7, 1.8 Hz, 1H), 7.33 (dd, J = 6.7, 4.8 Hz, 1H), 7.08 (d, J = 8.1 Hz,1H), 6.87 (t, J = 8.4 Hz, 2H), 6.02 (s, 1H), 4.64 (ddd, J = 42.9, 11.4,2.7 Hz, 2H), 3.35 (d, J = 16.6 Hz, 4H), 3.20-2.91 (m, 6H), 2.20 (s, 3H),2.04 (s, 3H), 1.15 (t, J = 7.3 Hz, 3H). 228 528.2 229 496.2 230 403.2231 445.2 232 459.2 233 473.2 234 475.2 235 471.2 ¹H NMR (500 MHz, DMSO)δ 8.72 (d, J = 7.0 Hz, 1H), 8.53 (d, J = 4.0 Hz, 1H), 7.76 (td, J = 7.7,1.7 Hz, 1H), 7.33 (dd, J = 6.8, 4.9 Hz, 1H), 7.02 (d, J = 8.1 Hz, 1H),6.85 (d, J = 8.1 Hz, 1H), 6.80 (d, J = 7.9 Hz, 1H), 5.80 (tz, 1H), 4.73(dd, J = 11.5, 1.6 Hz, 1H), 4.55 (q, J = 6.3 Hz, 1H), 4.49 (dd, J =11.5, 3.0 Hz, 1H), 4.31 (t, J = 7.8 Hz, 1H), 4.16 (t, J = 7.8 Hz, 1H),3.97 (dd, J = 7.9, 5.9 Hz, 1H), 3.75 (dd, J = 7.8, 6.0 Hz, 1H), 2.22 (s,3H), 2.05 (s, 3H), 1.48 (p, J = 6.3 Hz, 1H), 0.64 (d, J = 6.4 Hz, 4H).236 485.2 237 481.2 238 495.2 239 509.2 240 509.3 241 503.3 242 527.3243 487.2 ¹H NMR (300 MHz, CD₃OD) δ 8.59 (d, J = 4.9 Hz, 1H), 7.87-7.67(m, 1H), 7.36 (dd, J = 7.6, 4.9 Hz, 1H), 7.15 (d, J = 8.2 Hz, 1H), 6.96(d, J = 8.2 Hz, 1H), 6.79 (d, J = 7.9 Hz, 1H), 5.86 (s, 1H), 4.75-4.47(m, 2H), 3.75 (d, J = 11.2 Hz, 2H), 3.07 (t, J = 11.3 Hz, 2H), 2.26 (s,3H), 2.20-2.05 (m, 6H), 1.77 (d, J = 13.4 Hz, 2H), 1.43 (d, J = 12.5 Hz,1H), 1.22 (d, J = 9.3 Hz, 1H), 1.09 (t, J = 7.6 Hz, 3H). 244 501.2 ¹HNMR (500 MHz, DMSO) δ 8.54 (d, J = 4.2 Hz, 1H), 7.75 (td, J = 7.7, 1.7Hz, 1H), 7.57 (d, J = 7.6 Hz, 1H), 7.32 (dd, J = 7.0, 4.9 Hz, 1H), 7.05(d, J = 8.1 Hz, 1H), 6.86 (d, J = 8.1 Hz, 1H), 6.77 (d, J = 7.9 Hz, 1H),5.97 (t, 1H), 4.69 (dd, J = 11.5, 2.5 Hz, 1H), 4.54 (dd, J = 11.5, 3.0Hz, 1H), 3.75 (t, J = 11.1 Hz, 2H), 3.70-3.63 (m, 1H), 2.99 (t, J = 11.8Hz, 2H), 2.28 (p, J = 6.8 Hz, 1H), 2.21 (s, 3H), 2.04 (s, 3H), 1.65 (d,J = 10.0 Hz, 1H), 1.58 (d, J = 10.0 Hz, 1H), 1.40-1.30 (m, 1H),1.25-1.16 (m, 1H), 0.95 (dd, J = 6.8, 1.4 Hz, 6H). 246 487.3 248 523.3249 459.2 250 473.2 251 485.2 256 415.4 257 429.2 258 443.1 259 442.0260 442.2 261 442.2 262 454.0 263 498.3 264 421.0 265A 367.1 265B 367.1266A 383.1 266B 383.0 267A 426.9 428.9 267B 426.8 428.9 268 363.1 269A374.1 269B 374.2Biological Assay Protocols:

Example A1

BRD4 AlphaScreen™ Assay

BRD4-BD1 and BRD4-BD2 assays were conducted in white 384-wellpolystyrene plate in a final volume of 20 μL for BD1 and 40 μL for BD2.Inhibitors were first serially diluted in DMSO and added to the platewells before the addition of other reaction components. The finalconcentration of DMSO in the assay was 1.25% (BD1) and 0.83% (BD2). Theassays were carried out at room temperature for 75 min. in the assaybuffer (50 mM HEPES, pH 7.4, 100 mM NaCl, 0.05% CHAPS, 0.01% BSA),containing 50 nM Biotin-labeled tetra-acetylated histone H4 peptide(H4Ac4), 3.8 nM (BRD4-BD1, BPS Bioscience #31040) or 20 nM (BRD4-BD2,BPS Bioscience #31041). The reaction followed by the addition of 20 μLof assay buffer supplemented with Streptavidin donor beads (PerkinElmer6760002) and GSH Acceptor beads (PerkinElmer-AL109C) at 4 μg/mL underreduced light. After plate sealing, the plate was incubated in the darkat room temperature for 75 min. before reading on a PHERAstar FS platereader (BMG Labtech). IC₅₀ determination was performed by fitting thecurve of percent control activity versus the log of the inhibitorconcentration using the GraphPad Prism 5.0 software.

IC₅₀ data for the compounds of the Examples as determined by Assay A1 ispresented in Table 11.

TABLE 11 Example BRD4 BD-1 enzyme BRD4 BD-2 enzyme No. IC₅₀ (nM)* IC₅₀(nM)*  1A + +  1B ++ ++  2 + +  3 + +  4 + +  5 + +  6 + +  7 + +  8 + + 9 + + 10 ++ + 11 +++ ++ 12 ++ + 13 + + 14 +++ +++ 15 + + 17 + + 18A++ + 18B ++ + 21 + + 22 + + 23 + + 24A ++ + 24B ++ + 25 + + 26 + +27 + + 28 + + 29 + + 30 + + 31 + + 32 + + 33 +++ ++ 34 + + 35 ++ + 36++ + 37 ++ + 38 +++ ++ 39 + + 40 ++ + 49 + + 50 + + 51 + + 53 + + 54 + +55 + + 56 + + 57 + + 58 + + 59 + + 60 + + *Symbols used: +: IC₅₀ ≤100 nM++: 100 nM < IC₅₀ ≤ 1000 nM +++: 1000 nM to 10000 nM NT = not tested

Example A2

BRD4 AlphaScreen™ Assay

BRD4-BD1 and BRD4-BD2 assays were conducted in white 384-wellpolystyrene plate in a final volume of 40 μL for BD1 and 60 μL for BD2.Inhibitors were first serially diluted in DMSO and added to the platewells before the addition of other reaction components. The finalconcentration of DMSO in the assay was 1.25% (BD1) and 0.83% (BD2). Theassays were carried out at room temperature in the assay buffer (50 mMTris-HCl, pH 7.5, 0.01% Tween-20, 0.01% BSA, 5 mM DTT), containing 50 nMBiotin-labeled tetra-acetylated histone H4 peptide (H4Ac4) and BRD4-BD1or BRD4-BD2 protein at concentration less than 1 nM. The incubation for75 min. was followed by the addition of 20 μL of assay buffersupplemented with Streptavidin donor beads (PerkinElmer 6760002) and GSHAcceptor beads (PerkinElmer-AL109C) at final concentration 2-4 μg/mLunder reduced light. After plate sealing, the plate was incubated in thedark at room temperature for 75 min. before reading on a PHERAstar FSplate reader (BMG Labtech). IC₅₀ determination was performed by fittingthe curve of percent control activity versus the log of the inhibitorconcentration using the GraphPad Prism 5.0 software.

IC₅₀ data for the compounds of the Examples as determined by Assay A2 ispresented in Table 12.

TABLE 12 Example BRD4 BD-1 enzyme BRD4 BD-2 enzyme No. IC₅₀ (nM)* IC₅₀(nM)*  16 + +  19 + +  20 ++ +  41 + +  42 + +  43 + +  44 +++ ++ 45 + +  46 + +  47A ++ ++  47B ++ +  48A ++ +  48B ++ +  52 + + 61A + +  62B + +  63A ++ ++  69 + +  70 + +  71 ++ +  72 ++ +  73 ++ + 74 ++ +  75 + +  76 ++ ++  77 ++ ++  78 + +  79 +++ +++  80 +++ +++  81++ +  82 ++ +  83 + +  84 ++ +  85 +++ ++  86 ++ +  87 ++ +  88 + + 89 + +  90 + +  91 + +  92 + +  93 + +  94 + +  95 + +  96 + +  97 + + 98 + +  99 + + 100 + + 101A + + 101B + + 102 NT NT 103 + + 104 + +105 + + 106A + + 106B + + 107 + + 108 NT NT 109 + + 110 + + 111 + +112 + + 113A + + 113B + + 114A + + 114B + + 115 + + 116 + + 117 + +118 + + 119 + + 120 + + 121 ++ + 122 ++ + 123 ++ + 124 +++ ++ 125 +++ +126 ++ + 127 + + 128 + + 129 ++ + 130 + + 131 + + 132 + + 133 + +134 + + 135 + + 136 + + 137 +++ + 138 + + 139 + + 140 + + 141 + + 142++ + 143 ++ + 144A ++ + 144B ++ + 145 + + 146A + + 146B + + 146C + +147 + + 148 + + 149 + + 150 + + 151 + + 152 + + 153 + + 154 + + 155 + +156 ++ + 157 + + 158 + + 159A +++ ++ 159B + + 159C ++ + 159D + +159E + + 160A +++ ++ 160B +++ +++ 160C +++ +++ 160D +++ +++ 161 + +162 + + 163 + + 164 + + 165 + + 166 + + 167 + + 168A + + 168B + +169 + + 170A + + 170B + + 171 + + 172 + + 173 + + 174 + + 175 + +176 + + 177 + + 178 + + 179 + + 180A + + 180B + + 181A + + 181B + +182A + + 182B + + 183 + + 184 + + 185 ++ + 186 + + 187 + + 188 + +189 + + 190 + + 191 + + 192 + + 193A + + 193B + + 194 + + 195 + +196 + + 197 + + 198 +++ + 199 ++ + 200 ++ + 201A + + 201B + + 202A + +202B + + 203 + + 205 + + 206 + + 207 + + 208 + + 209 + + 210 + + 211 + +213 + + 214 + + 215 + + 216 + + 217 + + 218 + + 219 + + 220 + + 221 + +222 + + 224 + + 225 + + 226 + + 228 + + 229 + + 230 + + 231 + + 232 + +233 + + 234 + + 235 + + 236 + + 237 + + 238 + + 239 + + 240 + + 241 + +242 + + 243 + + 244 + + 246 + + 248 + + 249 + + 250 + + 251 + + 252 ++++ 253 ++ ++ 254 + + 255 + + 256 + + 257 ++ + 258 +++ ++ 259 ++ + 260++ + 261 ++ + 262 +++ + 263 ++ + 264 ++ + 265A +++ +++ 265B + + 266A++ + 266B +++ ++ 267A +++ +++ 267B + + 268 +++ ++ 269A + + 269B +++ +++*Symbols used: +: IC₅₀ ≤100 nM ++: 100 nM < IC₅₀ ≤ 1000 nM +++: 1000 nMto 10000 nM NT = not tested

Example B1: KMS.12.BM Cell Viability Assay

KMS.12.BM cell line (human myeloma) was purchased from JCRB (Osaka,Japan) and maintained in RPMI with 10% FBS culture medium. To measurethe cytotoxic activity of the compounds through ATP quantitation, theKMS.12.BM cells are plated in the RPMI culture medium at 5000cells/well/per 100 μL into a 96-well polystyrene clear black tissueculture plate (Greiner-bio-one through VWR, NJ), in the presence orabsence of a concentration range of test compounds. After 3 days, 100 mLCell Titer-GLO Luminescent (Promega, Madison, Wis.) cell culture agentis added to each well for 10 min. at room temperature to stabilize theluminescent signal. This determines the number of viable cells inculture based on quantitation of the ATP present, which signals thepresence of metabolically active cells. Luminescence is measured withthe Top Count 384 (Packard Bioscience through Perkin Elmer, Boston,Mass.). Compound inhibition is determined relative to cells culturedwith no drug and the IC₅₀ reported as the compound concentrationrequired for 50% cell death.

IC₅₀ data for the compounds of the Examples as determined by Assay B1 ispresented in Table 13.

TABLE 13 Example KMS cellular No. IC₅₀ (nM)*  1 +  1A +  1B NT  2 +  3 + 4 +  5 +  6 +  7 +  8 +  9 +  10 +  11 NT  12 ++  13 +  14 NT  15 + 16 +  17 +  18A +  18B +  19 +  20 +  21 +  22 +  23 +  24A ++  24B ++ 25 +  26 +  27 +  28 +  29 +  30 +  31 +  32 +  33 ++  34 +  35 +  36 + 37 +  38 NT  39 +  40 +  41 +  42 +  43 +  44 NT  45 +  46 +  47A NT 47B ++  48A NT  48B ++  49 +  50 +  51 +  52 +  53 +  54 +  55 +  56 + 57 +  58 +  59 +  60 +  61A +  62B +  62C +  63A ++  69-87 NT  88 + 89 +  90 +  91 +  92 +  93 +  94 +  95 +  96 +  97 +  98 NT  99 NT100 + 101A NT 101B NT 102 NT 103 + 104 + 105 NT 106A NT 106B NT 107 NT108 NT 109 + 110 + 111 + 112 + 113A NT 113B NT 114A NT 114B NT 115 NT116 NT 117 NT 118 NT 119 NT 120 + 121 + 122 + 123 + 124 NT 125 NT 126 +127 + 128 + 129 + 130 + 131 + 132 + 133 + 134 + 135 + 136 + 137 NT 138 +139 + 140 + 141 + 142 + 143 + 144A + 144B + 145 + 146A + 146B + 146C +147 + 148 + 149 + 150 + 151 + 152 + 153 + 154 + 155 + 156 + 157 + 158 +159A NT 159B + 159C ++ 159D + 159E + 160A NT 160B NT 160C NT 160D NT161 + 162 + 163 + 164 + 165 + 166 + 167 + 168A + 168B + 169 + 170A +170B + 171 + 172 + 173 + 174 + 175 + 176 + 177 + 178 + 179 + 180A +180B + 181A + 181B + 182A + 182B + 183 + 184 + 185 + 186 + 187 + 188 +189 + 190 + 191 + 192 + 193A + 193B + 194 + 195 + 196 + 197 + 198 NT 199NT 200 NT 201A + 201B + 202A + 202B + 203 + 205 + 206 + 207 + 208 +209 + 210 + 211 + 213 + 214 + 215 + 216 + 217 + 218 + 219 + 220 + 221 +222 + 224 + 225 + 226 + 228 + 229 + 230 + 231 + 232 + 233 + 234 + 235 +236 + 237 + 238 + 239 + 240 + 241 + 242 + 243 + 244 + 246 + 248 + 249 +250 + 251 + 252 NT 253 ++ 254 + 255 + 256 + 257 + 258 NT 259 ++ 260 ++261 NT 262 + 263 + 264 + 265A NT 265B + 266A + 266B NT 267A NT 267B +268 NT 269A + 269B NT *Symbols used: +: IC₅₀ ≤1000 nM ++: 1000 nM < IC₅₀≤ 10000 nM NT = not tested

Example C1

KMS.12.BM C-Myc ELISA Assay

KMS.12.BM cell line (human myeloma) was purchased from JCRB (Osaka,Japan) and maintained in RPMI with 10% FBS culture medium. To measurethe C-myc inhibitory activity of the compounds, the KMS.12.BM cells areplated in the RPMI culture medium at 75000 cells/well/per 200 μL into a96-well flat bottom polystyrene tissue culture plate (Corning throughVWR, NJ), in the presence or absence of a concentration range of testcompounds. After 2 h, cells are pelleted and lysed with Cell ExtractionBuffer (BioSource, Carlsbad, Calif.) in the presence of proteaseinhibitors (Life Technologies, Grand Island, N.Y. and Sigma, St Louis,Mo.). Clarified lyses are tested in a C-myc commercial ELISA (LifeTechnologies, Grand Island, N.Y.). Compound inhibition is determinedrelative to cells cultured with no drug and the IC₅₀ reported as thecompound concentration required for 50% C-myc inhibition.

IC₅₀ data for the compounds of the Examples as determined by Assay C1 ispresented in Table 14.

TABLE 14 Example KMS C-myc No. IC₅₀ (nM)*  1A +  1B NT  2 +  3 +  4 + 5 +  6 NT  7 +  8 +  9 +  10 +  11 NT  12 NT  13 +  14 NT  15 +  16 NT 17 NT  18A NT  18B NT  19 NT  20 NT  21 +  22 NT  23 NT  24A NT  24B NT 25 +  26 +  27 +  28 +  29 +  30 +  31 +  32 +  33 NT  34 +  35-49 NT 50 +  61A-63B NT  69-93 NT  94 +  95 +  96 +  97 NT  98 NT  99 NT 100NT 101A NT 101B NT 102 NT 103 NT 104 NT 105 NT 106A + 106B NT 107 NT 108NT 109 + 110 + 111 NT 112 NT 113A NT 113B NT 114A NT 114B NT 115 NT 116NT 117 NT 118 NT 119 NT 120 NT 121 NT 122 NT 123 NT 124 NT 125 NT 126 NT127 + 128 + 129 NT 130 + 131 NT 132 NT 133 + 134 + 135 + 136 + 137 NT138 + 139 ++ 140 + 141 + 142 + 143 NT 144A + 144B + 145-269B *Symbolsused: +: IC₅₀ ≤1000 nM ++: 1000 nM < IC₅₀ ≤ 10000 nM NT = not tested

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference cited in the presentdisclosure, including all patent, patent applications, and publications,is incorporated herein by reference in its entirety.

What is claimed is:
 1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

represents a double bond; L is O; Cy¹ is selected from phenyl or a 5-6membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatomsselected from N, O and S, wherein said phenyl or 5-6 membered heteroarylof Cy¹ is optionally substituted with 1, 2, 3, or 4 groups independentlyselected from R¹¹; R¹ and R² are independently selected from H, halo,CN, OH, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, OR^(a1),SR^(a1), C(═O)R^(b1), C(═O)NR^(c1)R^(d1), C(═O)OR^(a1), OC(═O)R^(b1),OC(═O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(═O)R^(b1),NR^(c1)C(═O)NR^(c1)R^(d1), NR^(c1)C(═O)OR^(a1), S(═O)R^(b1),S(═O)NR^(c1)R^(d1), S(═O)₂R^(b1), NR^(c1)S(═O))₂R^(b1) andS(═O)₂NR^(c1)R^(d1), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl of R¹ and R² are optionally substituted with 1, 2, or 3 groupsindependently selected from halo, CN, OH, OR^(a1), SR^(a1), C(═O)R^(b1),C(═O)NR^(c1)R^(d1), C(═O)OR^(a1), OC(═O)R^(b1), OC(═O)NR^(c1)R^(d1);NR^(c1)R^(d1), NR^(c1)C(═O)R^(b1), NR^(c1)C(═O)NR^(c1)R^(d1),NR^(c1)C(═O)R^(a1), S(═O)R^(b1), S(═O)NR^(c1)R^(d1); S(═O)₂R^(b1),NR^(c1)S(═O)₂R^(b1) and S(═O)₂NR^(c1)R^(d1); provided neither R¹ nor R²are Cl, Br, I, CN, or OH when L is O or S; alternatively, R¹ and R²together with the carbon atom to which they are attached are combined toform a C₃₋₇ cycloalkyl group, wherein said cycloalkyl group isoptionally substituted with 1, 2, 3, or 4 groups independently selectedfrom R²⁰; Cy³ is selected from phenyl, C₃₋₇ cycloalkyl, a 5-10 memberedheteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selectedfrom N, O and S, and a 4-10 membered heterocycloalkyl group comprisingcarbon and 1, 2, or 3 heteroatoms selected from N, O and S, wherein saidphenyl, C₃₋₇ cycloalkyl, 5-10 membered heteroaryl, and 4-10 memberedheterocycloalkyl of Cy³ is optionally substituted with 1, 2, 3, or 4groups independently selected from R¹³, wherein a ring-forming nitrogenatom of said 5-10 membered heteroaryl group or a ring-forming nitrogenatom of said 4-10 membered heterocycloalkyl group is optionallyoxidized; R⁴ is H, C(═O)NR^(14a)R^(14b), C(═O)R^(14a), C(═O)OR^(14a), orC₁₋₆ alkyl optionally substituted by 1, 2, or 3 substituentsindependently selected from halo, NR^(14a)R^(14b), OR^(14a), SR^(14a),CN, C(═O)R^(14a), C(═O)NR^(14a)R^(14b), C(═O)OR^(14a), OC(═O)R^(14b),OC(═O)NR^(14a)R^(14b), NR^(14a)C(═O)R^(14b),NR^(14a)C(═O)NR^(14a)R^(14b), NR^(14a)C(═O)OR^(14b), S(═O)R^(14a),S(═O)NR^(14a)R^(14b), S(═O)₂R^(14a), NR^(14a)S(═O)₂R^(14b), andS(═O)₂NR^(14a)R^(14b); R⁵ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, NR^(15a)R^(15b), —C(═O)NR^(15a)R^(15b),—C(═O)OR^(15a), phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl groupcomprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, O and S,and a 4-10 membered heterocycloalkyl group comprising carbon and 1, 2,or 3 heteroatoms selected from N, O and S, wherein said C₁₋₆ alkyl,phenyl, C₃₋₇ cycloalkyl, 5-6 membered heteroaryl, and 4-10 memberedheterocycloalkyl of R⁵ is optionally substituted by 1, 2, 3, or 4 groupsindependently selected from R¹⁵; R⁶ is absent; R⁷ is selected from H,halo, CN, OR^(a), NR^(c)R^(d), SR^(b), C(═O)NR^(c)R^(d), C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatomsselected from N, O and S, and a 4-7 membered heterocycloalkyl groupcomprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇cycloalkyl, 5-6 membered heteroaryl group, and a 4-7 memberedheterocycloalkyl group of R⁷ are optionally substituted with 1, 2, or 3groups independently selected from R¹⁷; R⁸ is selected from H, C₁₋₃alkyl, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, halo, CN, OR^(a),NR^(c)R^(d), SR^(b), and C(═O)NR^(c)R^(d), wherein said C₁₋₃ alkyl of R⁸is optionally substituted with 1, 2, or 3 groups independently selectedfrom R¹⁸; R⁹ and R^(9a) are independently selected from H, C₁₋₃ alkyl,C₁₋₃ haloalkyl, halo, CN, OR^(a), NR^(c)R^(d), SR^(b), andC(═O)NR^(c)R^(d); R¹¹ is independently at each occurrence selected fromH, C₁₋₃ alkyl, C₁₋₃ haloalkyl, halo, CN, OR^(a), NR^(c)R^(d), SR^(b),and C(═O)NR^(c)R^(d), wherein said C₁₋₃ alkyl is optionally substitutedby OH; R¹³ is independently at each occurrence selected from H, halo,CN, OH, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, OR^(a3),SR^(a3), C(═O)R^(b3), C(═O)NR^(c3)R^(d3), C(═O)OR^(a3), OC(═O)R^(b3),OC(═O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(═O)R^(b3),NR^(c3)C(═O)NR^(c3)R^(d3), NR^(c3)C(═O)OR^(a3), S(═O)R^(b3),S(═O)NR^(c3)R^(d3), S(═O)₂R^(b3), NR^(c3)S(═O)₂R^(b3) andS(═O)₂NR^(c3)R^(d3), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl of R¹³ is optionally substituted with 1, 2, or 3 groupsindependently selected from halo, CN, OH, OR^(a3), SR^(a3), C(═O)R^(b3),C(═O)NR^(c3)R^(d3), C(═O)OR^(a3), OC(═O)R^(b3), OC(═O)NR^(c3)R^(d3),NR^(c3)R^(d3), NR^(c3)C(═O)R^(b3), NR^(c3)C(═O)NR^(c3)R^(d3),NR^(c3)C(═O)OR^(a3), S(═O)R^(b3), S(═O)NR^(c3)R^(d3), S(═O)₂R^(b3),NR^(c3)S(═O)₂R^(b3) and S(═O)₂NR^(c3)R^(d3); R¹⁵ is independently ateach occurrence selected from H, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, halo, CN,OR^(a5), SR^(a5), C(═O)R^(b5), C(═O)NR^(c5)R^(d5), C(═O)OR^(a5),OC(═O)R^(b5), OC(═O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(═O)R^(b5),NR^(c5)C(═O)NR^(c5)R^(d5), NR^(c5)C(O)OR^(a5), S(═O)R^(b5),S(═O)NR^(c5)R^(d5), S(═O)₂R^(b5), NR^(c5)S(═O)₂R^(b5), andS(═O)₂NR^(c5)R^(d5), wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl are eachoptionally substituted by 1, 2, or 3 substituents independently selectedfrom halo, CN, OR^(a5), SR^(a5), C(═O)R^(b5), C(═O)NR^(c5)R^(d5),C(═O)OR^(a5), OC(═O)R^(b5), OC(═O)NR^(c5)R^(d5), NR^(c5)R^(d5),NR^(c5)C(═O)R^(b5), NR^(c5)C(═O)NR^(c5)R^(d5), NR^(c5)C(═O)OR^(a5),S(═O)R^(b5), S(═O)NR^(c5)R^(d5), S(═O)₂R^(b5), NR^(c5)S(═O)₂R^(b5),S(═O)₂NR^(c5)R^(d5), 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl, and C₃₋₇ cycloalkyl; R^(14a) and R^(14b) areindependently at each occurrence selected from H and C₁₋₆ alkyl, whereinsaid C₁₋₆ alkyl of R^(14a) and R^(14b) is optionally substituted with 1,2, or 3 substituents selected from R²⁰; or R^(14a) and R^(14b) togetherwith the N atom to which they are attached form a 4-7 memberedheterocycloalkyl ring optionally substituted with 1, 2, or 3substituents selected from R²⁰; R^(15a) and R^(15b) are independently ateach occurrence selected from H and C₁₋₆ alkyl, wherein said C₁₋₆ alkylof R^(15a) and R^(15b) is optionally substituted with 1, 2, or 3substituents selected from R²⁰; or R^(15a) and R^(15b) together with theN atom to which they are attached form a 4-7 membered heterocycloalkylring optionally substituted with 1, 2, or 3 substituents selected fromR²⁰; R¹⁷ and R¹⁸ are independently at each occurrence selected fromhalo, C₁₋₄ alkyl, CN, OR^(a), NR^(c)R^(d), SR^(b), C(═O)NR^(c)R^(d),C(═O)OR^(a), and NR^(c)C(═O)R^(a); R^(a), R^(c), and R^(d) areindependently at each occurrence selected from H, C₁₋₆ alkyl, C(O)R^(e),S(═O)₂R^(f), C(═O)NR^(g)R^(h), and phenyl optionally substituted by C₁₋₄alkoxy; R^(b) is at each occurrence C₁₋₆ alkyl; R^(e) is at eachoccurrence C₁₋₄ alkyl optionally substituted by a group selected fromphenyl, C₁₋₄ alkoxy, amino, C₁₋₄ alkylamino, and C₂₋₈ dialkylamino;R^(f) is C₁₋₄ alkyl; R^(g) and R^(h) are independently at eachoccurrence selected from H and C₁₋₄ alkyl; R^(a1), R^(b1), R^(c1) andR^(d1) are independently at each occurrence selected from H, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl, wherein said C₁₋₆ alkyl,C₂₋₆ alkenyl, and C₂₋₆ alkynyl forming R^(a1), R^(b1), R^(c1) and R^(d1)are each optionally substituted with 1, 2, or 3 substituentsindependently selected from R²⁰; R^(a3), R^(b3), R^(c3) and R^(d3) areindependently at each occurrence selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, and C₁₋₆ haloalkyl, wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl forming R^(a3), R^(b3),R^(c3) and R^(d3) are each optionally substituted with 1, 2, or 3substituents independently selected from halo, CN, OH, OR^(a4), SR^(a4),C(═O)R^(b4), C(═O)NR^(c4)R^(d4), C(═)OR^(a4), OC(═O)R^(b4),OC(═O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(═O)R^(b4),NR^(c4)C(═O)NR^(c4)R^(d4), NR^(c4)C(═O)OR^(a4), S(O)R^(b4),S(═O)NR^(c4)R^(d4), S(═O)₂R^(b4), NR^(c4)S(═O)₂R^(b4) andS(═O)₂NR^(c4)R^(d4); R^(a4), R^(b4), R^(c4) and R^(d4) are independentlyat each occurrence selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, and C₁₋₆ haloalkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, andC₂₋₆ alkynyl forming R^(a4), R^(b4), R^(c4) and R^(d4) are eachoptionally substituted with 1, 2, or 3 substituents independentlyselected from R²⁰; R^(a5), R^(b5), R^(c5) and R^(d5) are independentlyat each occurrence selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, 5-6 membered heterocycloalkyl, and C₁₋₆haloalkyl wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynylforming R^(a5), R^(b5), R^(c5) and R^(d5) are each optionallysubstituted with 1, 2, or 3 substituents independently selected fromR²⁰; or R^(c5) and R^(d5) together with the N atom to which they areattached form a 4-7 membered heterocycloalkyl ring optionallysubstituted with 1, 2, or 3 substituents independently selected fromR²⁰; and R²⁰ is at each occurrence independently selected from H, halo,OH, CN, amino, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ alkylamino,di(C₁₋₄ alkyl)amino, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₁₋₄ alkyl-C(═O)—,C₁₋₄ alkyl-C(═O)O—, C₁₋₄ alkyl-OC(═O)—, HOC(═O)—, H₂NC(═O)—, C₁₋₄alkyl-NHC(═O)—, di(C₁₋₄ alkyl)NC(═O)—, C₁₋₄ alkyl-C(═O)NH—, C₁₋₄alkyl-O—C(═O)NH—, C₁₋₄ alkyl-S(═O)—, H₂NS(═O)—, C₁₋₄ alkyl-NHS(═O)—,di(C₁₋₄ alkyl)NS(═O)—, C₁₋₄ alkyl-S(═O)₂—, C₁₋₄ alkyl-S(═O)₂NH—,H₂NS(═O)₂—, C₁₋₄ alkyl-NHS(═O)₂—, and di(C₁₋₄ alkyl)NS(═O)₂—.
 2. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein:

represents a double bond; L is O; Cy¹ is a five membered heteroarylgroup comprising carbon and 1, 2, 3 or 4 heteroatoms selected from N, Oand S, wherein said five membered heteroaryl of Cy¹ is optionallysubstituted with 1, 2, or 3 groups independently selected from R¹¹; R¹is selected from H, F, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, OR^(a1), C(═O)R^(b1), C(═O)NR^(c1)R^(d1), and C(O)OR^(a1); R²is selected from H, F, and C₁₋₆ alkyl; Cy³ is selected from phenyl, C₃₋₇cycloalkyl, a 5-10 membered heteroaryl group comprising carbon and 1, 2,3 or 4 heteroatoms selected from N, O and S, and a 4-10 memberedheterocycloalkyl group comprising carbon and 1, 2, or 3 heteroatomsselected from N, O and S, wherein said phenyl, C₃₋₇ cycloalkyl, 5-10membered heteroaryl, and 4-10 membered heterocycloalkyl of Cy³ isoptionally substituted with 1, 2, 3, or 4 groups independently selectedfrom R¹³; additionally, wherein a ring-forming nitrogen atom of said5-10 membered heteroaryl group or a ring-forming nitrogen atom of said4-10 membered heterocycloalkyl group is optionally oxidized; R⁴ is H orC₁₋₆ alkyl; R⁵ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, NR^(15a)R^(15b), phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatomsselected from N, O and S, and a 4-7 membered heterocycloalkyl groupcomprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S,wherein said C₁₋₆ alkyl, phenyl, C₃₋₇ cycloalkyl, 5-6 memberedheteroaryl, and 4-7 membered heterocycloalkyl of R⁵ is optionallysubstituted by 1, 2, 3, or 4 groups independently selected from R¹⁵; R⁶is absent; R⁷ is selected from H, halo, CN, C₁₋₆ alkyl, C₁₋₆ alkoxy,phenyl, and 5-6 membered heteroaryl group comprising carbon and 1, 2, 3or 4 heteroatoms selected from N, O and S, wherein said C₁₋₆ alkyl,phenyl, or 5-6 membered heteroaryl group, of R⁷ are optionallysubstituted with 1, 2, or 3 groups independently selected from R¹⁷; R⁸is selected from H, halo, CN, OH, and C₁₋₆ alkyl; R¹¹ is independentlyat each occurrence selected from H, C₁₋₃ alkyl, C₁₋₃ haloalkyl, halo,CN, OR^(a), NR^(c)R^(d), SR^(b), and C(═O)NR^(c)R^(d); R¹³ isindependently at each occurrence selected from H, halo, CN, OH, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, OR^(a3), SR^(a3),C(═O)R^(b3), C(═O)NR^(c3)R^(d3), C(═O)OR^(a3), OC(═O)R^(b3),OC(═O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(═O)R^(b3),NR^(c3)C(═O)NR^(c3)R^(d3), NR^(c3)C(═O)OR^(a3), S(═O)R^(b3),S(═O)NR^(c3)R^(d3), S(═O)₂R^(b3), NR^(c3)S(═O)₂R^(b3) andS(═O)₂NR^(c3)R^(d3), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl of R¹³ is optionally substituted with 1, 2, or 3 groupsindependently selected from halo, CN, OH, OR^(a3), SR^(a3), C(═O)R^(b3),C(═O)NR^(c3)R^(d3), C(═O)OR^(a3), OC(═O)R^(b3), OC(═O)NR^(c3)R^(d3),NR^(c3)R^(d3), NR^(c3)C(═O)R^(b3), NR^(c3)C(═O)NR^(c3)R^(d3),NR^(c3)C(═O)OR^(a3), S(═O)R^(b3), S(═O)NR^(c3)R^(d3), S(═O)₂R^(b3),NR^(c3)S(═O)₂R^(b3) and S(═O)₂NR^(c3)R^(d3); R¹⁵ is independently ateach occurrence selected from H, halo, CN, OH, OR^(a5), C(═O)R^(b5),C(═O)NR^(c5)R^(d5), C(═O)OR^(a5), NR^(c5)R^(d5), and NR^(c5)C(═O)R^(b5);R^(15a) and R^(15b) are independently selected from H and C₁₋₆ alkyl,wherein said C₁₋₆ alkyl of R^(15a) and R^(15b) is optionally substitutedwith 0, 1, 2, or 3 substituents selected from R²⁰; R¹⁷ is independentlyat each occurrence selected from halo, CN, OR^(a), NR^(c)R^(d), SR^(b),and C(═O)NR^(c)R^(d); R^(a), R^(c), and R^(d) are independently at eachoccurrence selected from H and C₁₋₆ alkyl; R^(b) is at each occurrenceC₁₋₆ alkyl; R^(a1), R^(b1), R^(c1) and R^(d1) are independently at eachoccurrence selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, andC₁₋₆ haloalkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynylforming R^(a1), R^(b1), R^(c1) and R^(d1) are each optionallysubstituted with 1, 2, or 3 substituents independently selected fromR²⁰; R^(a3), R^(b3), R^(c3) and R^(d3) are independently at eachoccurrence selected from H and C₁₋₆ alkyl, wherein said C₁₋₆ alkylforming R^(a3), R^(b3), R^(c3) and R^(d3) is optionally substituted with1, 2, or 3 substituents independently selected from halo, CN, OH,OR^(a4), SR^(a4), C(═O)R^(b4), C(═O)NR^(c4)R^(d4), C(═O)R^(a4),OC(═O)R^(b4), OC(═O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(═O)R^(b4),NR^(c4)C(═O)NR^(c4)R^(d4), NR^(c4)C(═O)OR^(a4), S(═O)R^(b4),S(═O)NR^(c4)R^(d4), S(═O)₂R^(b4), NR^(c4)S(═O)₂R^(b4) andS(═O)₂NR^(c4)R^(d4); R^(a4), R^(b4), R^(c4) and R^(d4) are independentlyat each occurrence selected from H and C₁₋₆ alkyl, wherein said C₁₋₆alkyl forming R^(a4), R^(b4), R^(c4) and R^(d4) is optionallysubstituted with 1, 2, or 3 substituents independently selected fromR²⁰; R^(a5), R^(b5), R^(c5) and R^(d5) are independently at eachoccurrence selected from H and C₁₋₆ alkyl, wherein said C₁₋₆ alkylforming R^(a5), R^(b5), R^(c5) and R^(d5) is optionally substituted with1, 2, or 3 substituents independently selected from R²⁰; and R²⁰ is ateach occurrence independently selected from H, halo, OH, CN, amino, C₁₋₄alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ alkylamino, di(C₁₋₄alkyl)amino, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₁₋₄ alkyl-C(═O)—, C₁₋₄alkyl-C(═O)O—, C₁₋₄ alkyl-OC(═O)—, HOC(═O)—, H₂NC(═O)—, C₁₋₄alkyl-NHC(═O)—, di(C₁₋₄ alkyl)NC(═O)—, C₁₋₄ alkyl-C(═O)NH—, C₁₋₄alkyl-S(═O)—, H₂NS(═O)—, C₁₋₄ alkyl-NHS(═O)—, di(C₁₋₄ alkyl)NS(═O)—,C₁₋₄ alkyl-S(═O)₂—, C₁₋₄ alkyl-S(═O)₂NH—, H₂NS(═O)₂—, C₁₋₄alkyl-NHS(═O)₂—, and di(C₁₋₄ alkyl)NS(═O)₂—.
 3. The compound of claim 1having Formula (Ia):

or a pharmaceutically acceptable salt thereof, wherein:

represents a double bond; Cy¹ is selected from isoxazolyl and pyrazolyl,wherein said isoxazolyl and pyrazolyl of Cy¹ is optionally substitutedwith 1 or 2 groups independently selected from R¹¹; R¹ is selected fromH, methyl, —C(═O)OCH₂CH₃, —C(═O)N(H)CH₂CH₃, —C(═O)N(H)CH₂CH₂OH, and—C(═O)N(CH₃)₂; Cy³ is selected from phenyl, pyridinyl, oxidopyridinyl,thiazolyl, cyclohexyl, dihydrobenzofuranyl and tetrahydrofuranyl,wherein said phenyl, pyridinyl, oxidopyridinyl, thiazolyl, cyclohexyl,dihydrobenzofuranyl and tetrahydrofuranyl of Cy³ is optionallysubstituted with 1, 2, 3, or 4 groups independently selected from R¹³;R⁵ is H, methyl, —CH═CH₂, —N(H)CH₃, —N(H)CH₂CH₃, —N(H)CH(CH₃)₂,—N(CH₃)₂, —N(H)CH₂CH₂OH, —N(H)CH(CH₃)CH₂OH, —N(H)CH₂CH(OH)CH₃,—N(H)C(CH₃)₂CH₂OH, —N(CH₃)CH₂CH₂OH, morpholinyl, pyrrolidinyl,hydroxypyrrolidinyl, piperidinyl, hydroxypiperidinyl, azetidinyl,hydroxyazetidinyl, piperazinyl, butoxycarbonylpiperazinyl, and phenyl;R⁶ is absent; R⁷ is selected from H, F, Cl, Br, methyl, methoxy, ethoxy,CN, phenyl, and pyridinyl; R¹¹ is independently at each occurrenceselected from H, methyl, ethyl, chloro, and methoxy; and R¹³ isindependently at each occurrence selected from H, F, CN, methoxy, —CF₃,—OCH₂C(═O)OH, —OCH₂C(═O)N(H)CH₂CH₃, —OCH₂C(═O)N(H)CH₂CH₂OH, and—OCH₂C(═O)N(CH₃)₂.
 4. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein Cy¹ is isoxazolyl substituted with 1 or2 groups independently selected from R¹¹.
 5. The compound of claim 1, ora pharmaceutically acceptable salt thereof, wherein Cy¹ is pyrazolylsubstituted with 1 or 2 groups independently selected from R¹¹.
 6. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R¹ is selected from H, methyl, —CH₂OH, —C(═O)OCH₂CH₃,—C(═O)N(H)CH₂CH₃, —C(═O)N(H)CH₃, —C(═O)NH₂, —C(═O)N(H)CH₂CH₂OH, and—C(═O)N(CH₃)₂.
 7. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R¹ is selected from H, methyl,—C(═O)OCH₂CH₃, —C(═O)N(H)CH₂CH₃, —C(═O)N(H)CH₂CH₂OH, and —C(═O)N(CH₃)₂.8. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R¹ is H.
 9. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R¹ is methyl.
 10. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R¹ is —C(═O)OCH₂CH₃.
 11. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R¹ is C(═O)N(H)CH₂CH₃.12. The compound of any claim 1, or a pharmaceutically acceptable saltthereof, wherein R¹ is C(═O)N(H)CH₂CH₂OH.
 13. The compound of claim 1,or a pharmaceutically acceptable salt thereof, wherein R¹ is—C(═O)N(CH₃)₂.
 14. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R¹ is —C(═O)N(H)CH₃.
 15. The compoundof claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹ is—C(═O)NH₂.
 16. The compound claim 1, or a pharmaceutically acceptablesalt thereof, wherein R¹ is —CH₂OH.
 17. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R² is H.
 18. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R² is methyl.
 19. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein Cy³ is selected from phenyl, pyridinyl,oxidopyridinyl, thiazolyl, cyclohexyl, dihydrobenzofuranyl,tetrahydrofuranyl, and piperinyl, wherein said phenyl, pyridinyl,oxidopyridinyl, thiazolyl, cyclohexyl, dihydrobenzofuranyl,tetrahydrofuranyl, and piperidinyl of Cy³ is optionally substituted with1, 2, 3, or 4 groups independently selected from R¹³.
 20. The compoundof claim 1, or a pharmaceutically acceptable salt thereof, wherein Cy³is selected from phenyl, pyridinyl, oxidopyridinyl, thiazolyl,cyclohexyl, dihydrobenzofuranyl and tetrahydrofuranyl, wherein saidphenyl, pyridinyl, oxidopyridinyl, thiazolyl, cyclohexyl,dihydrobenzofuranyl and tetrahydrofuranyl of Cy³ is optionallysubstituted with 1, 2, 3, or 4 groups independently selected from R¹³.21. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein Cy³ is phenyl optionally substituted with 1, 2, 3, or 4groups independently selected from R¹³.
 22. The compound of claim 1, ora pharmaceutically acceptable salt thereof, wherein Cy³ is pyridinyloptionally substituted with 1, 2, 3, or 4 groups independently selectedfrom R¹³.
 23. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein Cy³ is oxidopyridinyl optionally substituted with1, 2, 3, or 4 groups independently selected from R¹³.
 24. The compoundof claim 1, or a pharmaceutically acceptable salt thereof, wherein Cy³is thiazolyl optionally substituted with 1, 2, 3, or 4 groupsindependently selected from R¹³.
 25. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein Cy³ is cyclohexyloptionally substituted with 1, 2, 3, or 4 groups independently selectedfrom R¹³.
 26. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein Cy³ is dihydrobenzofuranyl optionally substitutedwith 1, 2, 3, or 4 groups independently selected from R¹³.
 27. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein Cy³ is tetrahydrofuranyl optionally substituted with 1, 2, 3, or4 groups independently selected from R¹³.
 28. The compound of claim 1,or a pharmaceutically acceptable salt thereof, wherein Cy³ ispiperidinyl optionally substituted with 1, 2, 3, or 4 groupsindependently selected from R¹³.
 29. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R⁴ is H, —C(═O)NH₂,—CH₂NH₂, —CH₂N(H)C(═O)CH₃, —C(═O)N(H)CH₃, —CH₂CH₃, or —CH₃.
 30. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R⁴ is H.
 31. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R⁵ is selected from H, C₁₋₄ alkyl,—CH═CH₂, NR^(15a)R^(15b), C(═O)NR^(15a)R^(15b), phenyl, and a 4-10membered heterocycloalkyl group comprising carbon and 1, 2, or 3heteroatoms selected from N, O and S, wherein said C₁₋₄ alkyl, and 4-10membered heterocycloalkyl of R⁵ is optionally substituted by 1 or 2groups independently selected from R¹⁵.
 32. The compound of claim 1, ora pharmaceutically acceptable salt thereof, wherein R⁵ is selected fromH, C₁₋₄ alkyl, —CH═CH₂, NR^(15a)R^(15b), C(═O)NR^(15a)R^(15b), phenyl,azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,1,2,3,6-tetrahydropyridinyl, 2,5-dihydro-1H-pyrrolyl, 1,4-diazepanyl,morpholinyl, and octahydropyrrolo[1,2-a]pyrazinyl, wherein said C₁₋₄alkyl, phenyl, azetidinyl, pyrolidinyl, piperidinyl, piperazinyl,1,2,3,6-tetrahydropyridinyl, 2,5-dihydro-1H-pyrrolyl, 1,4-diazepanyl,morpholinyl, and octahydropyrrolo[1,2-a]pyrazinyl of R⁵ is optionallysubstituted by 1 or 2 groups independently selected from R¹⁵.
 33. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R⁵ is H, methyl, —CH═CH₂, —N(H)CH₃, —N(H)CH₂CH₃, —N(H)CH(CH₃)₂,—N(CH₃)₂, —N(H)CH₂CH₂OH, —N(H)CH(CH₃)CH₂OH, —N(H)CH₂CH(OH)CH₃,—N(H)C(CH₃)₂CH₂OH, —N(CH₃)CH₂CH₂OH, morpholinyl, pyrrolidinyl,hydroxypyrrolidinyl, piperidinyl, hydroxypiperidinyl, azetidinyl,hydroxyazetidinyl, piperazinyl, butoxycarbonylpiperazinyl or phenyl. 34.The compound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R⁵ is selected from a 4-6 membered heterocycloalkyl groupcomprising carbon and 1, 2, or 3 heteroatoms selected from N, O and S,wherein said 4-6 membered heterocycloalkyl of R⁵ is optionallysubstituted by 1 or 2 groups independently selected from R¹⁵.
 35. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R⁵ is pyrrolidinyl, piperidinyl, azetidinyl, or piperazinyl,wherein said pyrrolidinyl, piperidinyl, azetidinyl, or piperazinyl of R⁵is optionally substituted by 1 or 2 groups independently selected fromR¹⁵.
 36. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R⁵ is pyrrolidinyl, wherein said pyrrolidinyl of R⁵ isoptionally substituted by 1 or 2 groups independently selected from R¹⁵.37. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R⁵ is piperidinyl, wherein said piperidinyl of R⁵ isoptionally substituted by 1 or 2 groups independently selected from R¹⁵.38. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R⁵ is azetidinyl, wherein said azetidinyl of R⁵ isoptionally substituted by 1 or 2 groups independently selected from R¹⁵.39. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R⁵ is piperazinyl, wherein said piperazinyl of R⁵ isoptionally substituted by 1 or 2 groups independently selected from R¹⁵.40. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R¹⁵ is independently at each occurrence selected fromC₁₋₆ alkyl, CN, OR^(a5), C(═O)R^(b5), C(═O)NR^(c5)R^(d5), C(═O)OR^(a5),NR^(c5)R^(d5), NR^(c5)C(═O)R^(b5), NR^(c5)C(═O)NR^(c5)R^(d5),NR^(c5)C(═O)OR^(a5), S(═O)₂R^(b5), NR^(c5)S(═O)₂R^(b5), andS(═O)₂NR^(c5)R^(d5), wherein said C₁₋₆ alkyl, is optionally substitutedby 1, 2, or 3 substituents independently selected from halo, CN,OR^(a5), SR^(a5), C(═O)R^(b5), C(═O)NR^(c5)R^(d5), C(═O)OR^(a5),OC(═O)R^(b5), OC(═O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(═O)R^(b5),NR^(c5)C(═O)NR^(c5)R^(d5), NR^(c5)C(═O)OR^(a5), S(═O)R^(b5),S(═O)NR^(c5)R^(d5), S(═O)₂R^(b5), NR^(c5)S(═O)₂R^(b5),S(═O)₂NR^(c5)R^(d5), 5-6 membered heteroaryl, 4-7 memberedheterocycloalkyl, phenyl, and C₃₋₇ cycloalkyl.
 41. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein IC is selectedfrom H, halo, CN, NR^(c)R^(d), C₁₋₆ alkyl, C₂₋₆ alkenyl, 5-6 memberedheteroaryl group comprising carbon and 1, 2, 3 or 4 heteroatoms selectedfrom N, O and S, and a 5-6 membered heterocycloalkyl group comprisingcarbon and 1, 2, or 3 heteroatoms selected from N, O and S, wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, 5-6 membered heteroaryl group, and 5-6membered heterocycloalkyl group of IC are optionally substituted with 1,2, or 3 groups independently selected from R¹⁷.
 42. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein R⁷selected from H, F, Cl, Br, CN, NR^(c)R^(d), C₁₋₄ alkyl, C₂₋₄ alkenyl,pyrazolyl, pyridinyl, pyrimidinyl, and 1,2,3,6-tetrahydropyridinyl,wherein said C₁₋₄ alkyl, C₂₋₄ alkenyl, pyrazolyl, pyridinyl,pyrimidinyl, and 1,2,3,6-tetrahydropyridinyl of R⁷ are optionallysubstituted with 1, 2, or 3 groups independently selected from R¹⁷. 43.The compound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R⁷ is selected from H, halo, C₁₋₄ alkyl, and CN.
 44. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R⁷ is selected from H, Br, methyl, and CN.
 45. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein R⁷ is H.46. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R⁷ is Br.
 47. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R⁷ is methyl.
 48. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R⁷ is CN.
 49. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is selected from H, halo, C₁₋₄alkyl, and CN.
 50. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is H.
 51. The compound of claim 1,or a pharmaceutically acceptable salt thereof, having Formula (IIIb):


52. The compound of claim 1, or a pharmaceutically acceptable saltthereof, having Formula (IVb):


53. The compound of claim 1 selected from:7-(3,5-dimethylisoxazol-4-yl)-2-methyl-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;7-(3,5-Dimethylisoxazol-4-yl)-N-isopropyl-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-amine;7-(3,5-Dimethylisoxazol-4-yl)-N-methyl-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-amine;7-(3,5-Dimethylisoxazol-4-yl)-N-ethyl-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-amine;7-(3,5-Dimethylisoxazol-4-yl)-N,N-dimethyl-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-amine;2-{[7-(3,5-Dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]amino}ethanol;2-{[7-(3,5-Dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]amino}propan-1-ol;1-{[7-(3,5-Dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]amino}propan-2-ol;2-1[7-(3,5-Dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]amino-2-methylpropan-1-ol;2-[[7-(3,5-Dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl](methyl)amino]ethanol;7-(3,5-Dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-2-piperazin-1-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;7-(3,5-dimethylisoxazol-4-yl)-2,4-diphenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;7-(3,5-Dimethylisoxazol-4-yl)-2-morpholin-4-yl-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;7-(3,5-Dimethylisoxazol-4-yl)-4-phenyl-2-pyrrolidin-1-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;1-[7-(3,5-Dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-ol;7-(3,5-Dimethylisoxazol-4-yl)-4-phenyl-2-piperidin-1-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;1-[7-(3,5-Dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperidin-4-ol;1-[7-(3,5-Dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperidin-3-ol;1-[7-(3,5-Dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]azetidin-3-ol;and4-[7-(3,5-Dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperazine-1-carboxylate;or a pharmaceutically acceptable salt thereof.
 54. The compound of claim1, selected from:(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-2-vinyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;(1R)-1-[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]ethane-1,2-diol;1-[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]ethanol;(4S)-7-(3,5-Dimethylisoxazol-4-yl)-N,N-dimethyl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine-2-carboxamide;(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;tert-Butyl(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine-2-carboxylate;(4S)-7-(3,5-Dimethylisoxazol-4-yl)-2-(morpholin-4-ylcarbonyl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;(4S)-7-(3,5-Dimethylisoxazol-4-yl)-N-methyl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine-2-carboxamide;(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine-2-carboxamide;tert-Butyl4-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]-3,6-dihydropyridine-1(2H)-carboxylate;tert-Butyl3-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]-2,5-dihydro-1H-pyrrole-1-carboxylate;tert-Butyl5-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]-3,6-dihydropyridine-1(2H)-carboxylate;tert-Butyl4-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperidine-1-carboxylate;tert-Butyl3-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidine-1-carboxylate;tert-Butyl3-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperidine-1-carboxylate;(4S)-2-(1-Acetylpiperidin-4-yl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-2-(1,2,3,6-tetrahydropyridin-4-yl)-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;(4S)-2-(2,5-dihydro-1H-pyrrol-3-yl)-′7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-2-pyrrolidin-3-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-2-(1,2,5,6-tetrahydropyridin-3-yl)-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-piperidin-3-yl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;(4S)-2-(1-Acetylpiperidin-4-yl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;(4S)-2-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;(4S)-2-[1-(cyclopropylcarbonyl)piperidin-4-yl]-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-[1-(methylsulfonyl)piperidin-4-yl]-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;(4S)-2-(1-acetylpyrrolidin-3-yl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;(4S)-2-[1-(cyclopropylcarbonyl)pyrrolidin-3-yl]-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-[1-(methylsulfonyl)pyrrolidin-3-yl]-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;(4S)-2-(1-acetyl-1,2,5,6-tetrahydropyridin-3-yl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;(4S)-2-(1-acetylpiperidin-3-yl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;(4S)-2-[1-(cyclopropylcarbonyl)piperidin-3-yl]-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-[1-(methylsulfonyl)piperidin-3-yl]-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;(3R)-1-[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]-N-isopropylpyrrolidine-3-carboxamide;1-[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]-3-methylpyrrolidin-3-ol;4-[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]-1,4-diazepane-1-sulfonamide;(4S)-2-(4-Acetyl-1,4-diazepan-1-yl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;(4S)-7-(3,5-Dimethylisoxazol-4-yl)-2-[4-(methylsulfonyl)-1,4-diazepan-1-yl]-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;(4S)-7-(3,5-Dimethylisoxazol-4-yl)-2-piperazin-1-yl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;2-{4-[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperazin-1-yl}-N,N-dimethylacetamide;2-Cyano-N-{(3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-yl}-N-methylacetamide;N-{(3R)-1-[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-yl}morpholine-4-carboxamide;7-(3,5-Dimethylisoxazol-4-yl)-2-methyl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;Methyl{(3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-yl}carbamate;7-(3,5-Dimethylisoxazol-4-yl)-9-fluoro-N,N-dimethyl-4-pyridin-3-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-amine;1-[7-(3,5-Dimethylisoxazol-4-yl)-9-fluoro-4-pyridin-3-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-ol;7-(3,5-Dimethylisoxazol-4-yl)-N-ethyl-9-fluoro-4-pyridin-3-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-amine;(3R)-1-[7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-3-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-ol;1-[7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-3-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]azetidin-3-ol;(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-morpholin-4-yl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-2-pyrrolidin-1-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-(4-methylpiperazin-1-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;(4S)-2-azetidin-1-yl-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]azetidin-3-ol;4-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]-1-methylpiperazin-2-one;ethyl4-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperazine-1-carboxylate;(3R)-1-[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-3-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-ol;(3S)-1-[(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-3-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-ol;1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperidin-4-ol;(3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperidin-3-ol;(3S)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperidin-3-ol;1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]-N,N-dimethylpiperidin-4-amine;4-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperazin-2-one;(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-[4-(methylsulfonyl)piperazin-1-yl]-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-(4-isopropylpiperazin-1-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperidine-4-carbonitrile;{1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperidin-4-yl}methanol;2-{4-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperazin-1-yl}ethanol;(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-(4-phenylpiperazin-1-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;(4S)-2-(4-benzylpiperazin-1-yl)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;(3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]-N,N-dimethylpyrrolidin-3-amine;(3S)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]-N,N-dimethylpyrrolidin-3-amine;(3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]-N-methylpyrrolidin-3-amine;(3S)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]-N-methylpyrrolidin-3-amine;tert-butyl{(3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-yl}carbamate;tert-butyl{(3S)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-yl}carbamate;(4S)-2-[4-(cyclopropylmethyl)piperazin-1-yl]-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-[4-(2-methoxyethyl)piperazin-1-yl]-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;2-[[7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl](methyl)amino]ethanol;7-(3,5-dimethylisoxazol-4-yl)-N-methyl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-amine;7-(3,5-dimethylisoxazol-4-yl)-N,N-dimethyl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-amine;1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperidine-4-carboxamide;1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]-N-methylpiperidine-4-carboxamide;N-{1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperidin-4-yl}acetamide;2-{4-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperazin-1-yl}acetamide;(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-(4-ethylpiperazin-1-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]-4-methylpiperidin-4-ol;4-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]-3-methylpiperazin-2-one;tert-butyl{1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]azetidin-3-yl}carbamate;tert-butyl4-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]-1,4-diazepane-1-carboxylate;2-{[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]amino}ethanol;tert-butyl(2-{[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]amino}ethyl)carbamate;N-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]ethane-1,2-diamine;N-{(3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-yl}acetamide;N-{(3S)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-yl}acetamide;(3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-amine;(3S)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-amine;N-{(3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-yl}-2,2,2-trifluoroacetamide;N-{(3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-yl}-2-methoxyacetamide;N-{(3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-yl}cyclopropanecarboxamide;N-{(3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-yl}methanesulfonamide;N-{(3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-yl}propanamide;N-{(3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-yl}-2-methylpropanamide;N-{(3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-yl}cyclobutanecarboxamide;2-cyano-N-{(3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-yl}acetamide;N-{(3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-yl}tetrahydro-2H-pyran-4-carboxamide;N-{(3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-yl}ethanesulfonamide;N-{(3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-yl}propane-1-sulfonamide;N′-{(3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-yl}-N,N-dimethylurea;N-{(3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-yl}propane-2-sulfonamide;N-{(3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-yl}cyclopropanesulfonamide;methyl{(3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-yl}methylcarbamate;N-{(3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-yl}-N-methylmethanesulfonamide;N-{(3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-yl}-2-methoxy-N-methylacetamide;N-{(3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidin-3-yl}-N-methylacetamide;(4S)-2-(4-acetylpiperazin-1-yl)-′7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-(4-propionylpiperazin-1-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-[4-(ethylsulfonyl)piperazin-1-yl]-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-[4-(2-oxo-2-pyrrolidin-1-ylethyl)piperazin-1-yl]-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;4-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperazine-1-sulfonamide;1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]azetidin-3-amine;N-{1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]azetidin-3-yl}acetamide;N-{1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]azetidin-3-yl}propanamide;N-{1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]azetidin-3-yl}-2-methylpropanamide;N-{1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]azetidin-3-yl}-2-methoxyacetamide;N-{1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]azetidin-3-yl}cyclopropanecarboxamide;N-{1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]azetidin-3-yl}cyclobutanecarboxamide;N-{1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]azetidin-3-yl}methanesulfonamide;N-{1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]azetidin-3-yl}ethanesulfonamide;N-{1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]azetidin-3-yl}propane-2-sulfonamide;N-{1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperidin-4-yl}methanesulfonamide;N-{1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperidin-4-yl}-2-methoxyacetamide;N-{1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperidin-4-yl}-2,2,2-trifluoroacetamide;N-{1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperidin-4-yl}propanamide;N-{1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperidin-4-yl}propanamide;(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-(4-propionyl-1,4-diazepan-1-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;(4S)-7-(3,5-dimethylisoxazol-4-yl)-2-[4-(ethylsulfonyl)-1,4-diazepan-1-yl]-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine;(3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]-N-methylpyrrolidine-3-carboxamide;(3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]-N-ethylpyrrolidine-3-carboxamide;and(3R)—N-cyclopropyl-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]pyrrolidine-3-carboxamide;or a pharmaceutically acceptable salt thereof.
 55. A pharmaceuticalcomposition comprising a compound of claim 1, or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptablecarrier.
 56. A method of inhibiting a BET protein in vitro comprisingcontacting a compound of claim 1, or a pharmaceutically acceptable saltthereof, with said BET protein.